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CAS No. : | 178752-79-9 | MDL No. : | MFCD01318996 |
Formula : | C8H12BNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YZQQHZXHCXAJAV-UHFFFAOYSA-N |
M.W : | 165.00 | Pubchem ID : | 2762527 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 50.47 |
TPSA : | 43.7 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) : | -6.63 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.95 |
Log Po/w (WLOGP) : | -0.57 |
Log Po/w (MLOGP) : | 0.33 |
Log Po/w (SILICOS-IT) : | -1.2 |
Consensus Log Po/w : | -0.1 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.7 |
Solubility : | 3.3 mg/ml ; 0.02 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.45 |
Solubility : | 5.79 mg/ml ; 0.0351 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.39 |
Solubility : | 6.72 mg/ml ; 0.0407 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.84 |
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 |
---|---|---|
61% | Stage #1: With n-butyllithium; Trimethyl borate In tetrahydrofuran; hexanes at -78 - -20℃; for 1.41667 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexanes; water for 0.0833333 h; |
3-Bromo-N,N-dimethylaniline (500 mg, 2.50 mmol) was dissolved in THF (8 mL) and the solution was cooled to -78° C. n-Butyllithium (1.6M in hexanes, 1.56 mL, 3.75 mmol) was added drop-wise at -78° C. and the reaction mixture was stirred at this temperature for another 5 min. Trimethylborate (1.11 mL, 10.0 mmol) was added and the mixture was stirred for 1 h at -78° C. and was then left to warm to -20° C. over a period of 20 min. 2M HCl (3 mL) was added and the mixture was stirred for 5 min and was then neutralized by the addition of sat. NaHCO3 solution. The mixture was extracted with AcOEt (3.x.10 mL) and the combined organics were concentrated under reduced pressure to provide the crude boronic acid. Flash chromatography on silica gel eluting with acetone/CH2Cl2 1:1 provided 3-dimethylaminophenylboronic acid (251 mg, 61percent). |
61% | Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.0833333 h; Stage #2: With Trimethyl borate In tetrahydrofuran; hexanes at -78 - -20℃; for 1.33 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexanes for 0.0833333 h; |
[0230] (a) 3-Dimethylaminophenylboronic acid. 3-Bromo-N,N- dimethylaniline (500 mg, 2.50 mmol) was dissolved in THF (8 mL) and the solution was cooled to -78°C. n-Butyllithium (1.6M in hexanes, 1.56 mL, 3.75 mmol) was added drop- wise at -780C and the reaction mixture was stirred at this temperature for another 5 min. Trimethylborate (1.11 mL, 10.0 mmol) was added and the mixture was stirred for 1 h at -78°C and was then left to warm to -20°C over a period of 20 min. 2M HCl (3 mL) was added and the mixture was stirred for 5 min and was then neutralized by the addition of sat. NaHCO3 solution. The mixture was extracted with AcOEt (3x10 mL) and the combined organics were concentrated under reduced pressure to provide the crude boronic acid. Flash chromatography on silica gel eluting with acetone/CH2Cl2 1:1 provided 3-dimethylaminophenylboronic acid (251 mg, 61percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 75℃; for 24h; | Example 3: 2-(3-Dimethylamino-phenyl)-4,6-bis-(4-fluoro-3-trifluoromethyl-phenoxy)- pyrimidin-5-ylamine; 23g of 2-Bromo-4,6-bis-(4-fluoro-3-trifluoromethyl-phenoxy)-pyrimidin-5-ylamine are dissolved under nitrogen together with 10.7g of 3-(N,N-dimethylamino) phenylboronic acid, 0.4g of tris(dibenzylideneacetone)dipalladium, 27.5g of K3PO4 and 0.7g of 2-dicyclohexyl- phosphino-2',6'-dimethoxybiphenyl in 450ml of toluene. The mixture is heated at 75C for 24h, diluted with diethylether, washed with water and then dried over MgSO4. The solvents are removed under vacuum. 14.8g of the title compound are isolated as white powder (mp. 110-11 1 C) after purification by filtration and recrystallization from cyclohexane. | |
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 75℃; for 24h;Inert atmosphere; | Example 3: 2-(3-Dimethylamino-phenyl)-4,6-bis-(4-fluoro-3-trifluoromethyl-phenoxy)- pyrimidin-5-ylamine 23g of 2-Bromo-4,6-bis-(4-fluoro-3-trifluoromethyl-phenoxy)-pyrimidin-5-ylamine are dissolved under nitrogen together with 10.7g of 3-(N,N-dimethylamino) phenylboronic acid, 0.4g of tris(dibenzylideneacetone)dipalladium, 27.5g of K3P04 and 0.7g of 2-dicyclohexyl- PAT054251 -WO-PCT - 31 - phosphino-2',6'-dimethoxybiphenyl in 450ml of toluene. The mixture is heated at 75C for 24h, diluted with diethylether, washed with water and then dried over MgS04. The solvents are removed under vacuum. 14.8g of the title compound are isolated as white powder (mp. 1 10-1 1 1 C) after purification by filtration and recrystallization from cyclohexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 180℃; for 0.0194444h;Microwave Irradiation; | 5-t-Butyl-7-iodo-1-phenylbenzimidazole (94 mg, 0. 25mol), toluene (1.5 ml), tetrakis (triphenylphosphine) palladium (0) (15 mg, 0.0125 mmol), 3-dimethylamino- phenylboronic acid (41 mg, 0.25 mmol), ethanol (1.5 ml) and potassium carbonate (1M in water, 0.5 ml, 69 mg, 0.5 mmol) were added sequentially to a Smith Process Via) under nitrogen and irradiated for 70 s at 180 C (150 W initial power) using a Personal Chemistry Smith Creator microwave. The tube was blown dry with nitrogen and the solid residue dissolved in dimethylsulphoxide (2 ml) and eluted through a prep LCMS column to give, after removal of the solvent, the desired product as a glass (102 mg, 42%) m/z, 370.5 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene;Heating / reflux; | 5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol), 3-dimethylaminophenyl- boronic acid (82 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and crude product was purified on a 2 g silica IsoluteO SPE column, eluting with dichloromethane/methanol (95: 5). The eluent was concentrated under reduced pressure and the crude product was suspended in acetonitrile then treated with diethyl ether to precipitate the product. Recrystallisation from diethyl ether afforded the title compound (64 mg, 38%) m/z, 339.0 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | EXAMPLE 57 5-Methyl-thiophene-2-carboxylic acid [7-(3-dimethylamino-phenyl)-4-methoxy-benzo-thiazol-2-yl]-amide 5-Methyl-thiophene-2-carboxylic acid [7-(3-dimethylamino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is synthesised from 5-methyl-thiophene-2-carboxylic acid (7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and 3-dimethylaminophenylboronic acid (58 mg, 0.35 mmol) using the general procedure A as a light yellow solid in 71% yield. MS: m/e=424 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In ethanol; | EXAMPLE 9 Boronic acid, [3-(dimethylamino)phenyl]- To a -78 C. solution of n-butyllithium (4.8 ml of a 2.5 molar solution in hexanes; 12 mmol) in ether (5 ml) was added 3-bromo-N,N-dimethylaniline (1.72 g, 10.0 mmol, Giumanini, A. G., Chiavari, G., Musiani, M. M., Rossi, P., Synthesis, 1980, 743.) dropwise. Five minutes later, a solution of trimethylborate (1.35 ml 13 mmol) in 5 ml. of ether was added dropwise over 10 minutes. The reaction was stirred for 1 hour then warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (20 ml), and concentrated in vacuo. To the residue was added glacial acetic acid (HOAc) (1.5 ml) and EtOH (20 ml). The resulting mixture was then heated at reflux for 30 minutes, and concentrated in vacuo. The residue (3.16 g) was a clear yellow oil which solidified to a thick white gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage A By carrying out the reaction as in Stage C of Example 45, but from 2.5 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate, from 0.30 g of tetrakis(triphenylphosphine)palladium, from 0.77 g of 3-N,N-dimethylaminophenylboronic acid, obtained in the trimeric anhydride form, and from 20 cm3 of a 2M aqueous sodium carbonate solution at reflux for seven hours in 20 cm3 of toluene and 10 cm3 of methanol, 2.09 g (85%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-(3-N,N-dimethylaminophenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of an orange-coloured pasty solid, used in the following stage, the characteristic of which was as follows: mass spectrum (EI): M/Z=466 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | 3-Bromo-N,N-dimethylaniline (500 mg, 2.50 mmol) was dissolved in THF (8 mL) and the solution was cooled to -78 C. n-Butyllithium (1.6M in hexanes, 1.56 mL, 3.75 mmol) was added drop-wise at -78 C. and the reaction mixture was stirred at this temperature for another 5 min. Trimethylborate (1.11 mL, 10.0 mmol) was added and the mixture was stirred for 1 h at -78 C. and was then left to warm to -20 C. over a period of 20 min. 2M HCl (3 mL) was added and the mixture was stirred for 5 min and was then neutralized by the addition of sat. NaHCO3 solution. The mixture was extracted with AcOEt (3×10 mL) and the combined organics were concentrated under reduced pressure to provide the crude boronic acid. Flash chromatography on silica gel eluting with acetone/CH2Cl2 1:1 provided 3-dimethylaminophenylboronic acid (251 mg, 61%). | |
61% | [0230] (a) 3-Dimethylaminophenylboronic acid. 3-Bromo-N,N- dimethylaniline (500 mg, 2.50 mmol) was dissolved in THF (8 mL) and the solution was cooled to -78C. n-Butyllithium (1.6M in hexanes, 1.56 mL, 3.75 mmol) was added drop- wise at -780C and the reaction mixture was stirred at this temperature for another 5 min. Trimethylborate (1.11 mL, 10.0 mmol) was added and the mixture was stirred for 1 h at -78C and was then left to warm to -20C over a period of 20 min. 2M HCl (3 mL) was added and the mixture was stirred for 5 min and was then neutralized by the addition of sat. NaHCO3 solution. The mixture was extracted with AcOEt (3x10 mL) and the combined organics were concentrated under reduced pressure to provide the crude boronic acid. Flash chromatography on silica gel eluting with acetone/CH2Cl2 1:1 provided 3-dimethylaminophenylboronic acid (251 mg, 61%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 20℃;Heating / reflux; | A round bottom flask was charged with (3-benzyloxy-5-bromo-phenyl)-pyridin-3-yl-amine (200 mg, 0.56 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol). 1,2-Dimethoxyethane (5 mL) was added under argon and the mixture was stirred for 10 min at room temperature. A solution of 3-dimethylamino-phenylboronic acid (110 mg, 0.67 mmol) in ethanol/DME 1:2 (2.5 mL) and 2M aqueous Na2CO3 (0.56 mL, 1.12 mmol) were added and the mixture was heated at reflux overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered over Hyflo and the filter cake washed with ethyl acetate (2×5 mL). The filtrate was concentrated under reduced pressure and the oily residue was taken up in brine/AcOEt 1:1 (20 mL). The layers were separated and the aqueous layer was extracted with AcOEt (10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the crude material (260 mg). Flash chromatography on silica gel (12 g, AcOEt/heptane 2:1) provided pure 3-benzyloxy-3'-dimethylamino-5-(pyridin-3-ylamino)-biphenyl (169 mg, 76%) as a yellow oil. |
76% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water;Heating / reflux; | (b) 3-Benzyloxy-3'-dimethylamino-5-(pyridin-3-ylamino)-biphenyl. A round bottom flask was charged with (3-benzyloxy-5-bromo-phenyl)-pyridin-3-yl-amine (200 mg, 0.56 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol). 1,2-Dimethoxyethane (5 mL) was added under argon and the mixture was stirred for 10 min at room temperature. A solution of 3-dimethylamino-phenylboronic acid (110 mg, 0.67 mmol) in ethanol/DME 1:2 (2.5 mL) and 2M aqueous Na2CO3 (0.56 mL, 1.12 mmol) were added and the mixture was heated at reflux overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered over Hyflo and the filter cake washed with ethyl acetate (2×5 mL). The filtrate was concentrated under reduced pressure and the oily residue was taken up in brine/AcOEt 1:1 (20 mL). The layers were separated and the aqueous layer was extracted with AcOEt (10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the crude material (260 mg). Flash chromatography on silica gel (12 g, AcOEt/heptane 2:1) provided pure 3-benzyloxy-3'-dimethylamino-5-(pyridin-3-ylamino)-biphenyl (169 mg, 76%) as a yellow oil. |
76% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water;Heating / reflux; | 0231] (b) 3-Benzyloxy-3'-dimethylammo-5-(pyridin~3-ylamino)-biphenyl. A round bottom flask was charged with (3-benzyloxy-5-bromo-phenyl)-pyridin- 3-yl-amine (200 mg, 0.56 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol). 1,2-Dimethoxyethane (5 mL) was added under argon and the mixture was stirred for 10 min at room temperature. A solution of 3- dimethylamino-phenylboronic acid (110 mg, 0.67 mmol) in ethanol/DME 1:2 (2.5 mL) and 2M aqueous Na2CO3 (0.56 mL, 1.12 mmol) were added and the mixture was heated at reflux overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered over Hyflo and the filter cake washed with ethyl acetate (2x5 mL). The filtrate was concentrated under reduced pressure and the oily residue was taken up in brine/AcOEt 1:1 (20 mL). The layers were separated and the aqueous layer was extracted with AcOEt (10 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to give the crude material (260 mg). Flash chromatography on silica gel (12 g, AcOEt/heptane 2:1) provided pure <n="70"/>3-benzyloxy-3'-dimethylamino-5-(rhoyridin-3-ylamino)-biplienyl (169 mg, 76%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; toluene;Heating / reflux; | 4. General procedure to make 6-chloro-3-substituted-imidazof1,2- blpyridazin[0160] A reaction mixture containing 3-bromo-6-chloro- imidazo[1 ,2-b]pyridazine (0.43 mmol), Boronic acid (0.43 mmol), Pd(PhP3)4 (7.74 umol, 0.018 eq) and NaCO3 (2M, 0.43 mmol) in 5 ml_ of toluene-MeOH (4:1) was degassed with Ar for 10 min. The reaction was refluxed overnight. The mixture was filtered through MgSO4 and concentrated under vacuum. The residue was purified by combiflash (0% to 70 EtOAc/Hexane) to give desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; toluene; for 4h;Heating / reflux; | 4-((2-dimethylamino)-6-(3-(dimethylamino)phenyl)quinazolin-4- ylamino)methyl)N-4-fluorophenyl)benzamide was prepared starting from N-(4-((2- (dimethylamino)-6-iodoquinazolin-4-ylamino)methyl)phenyl)-4-fluorobenzamide (0.53 g, 0.98 mmol), 3-(dimethylamino)phenylboronic acid (0.16 g, 0.98 mmol) tetrakis(triphenylphosphine)palladium (0) (50 mg, 0.0551 mmol), Toluene (8 mL), methanol (2 mL), sodium carbonate (2.0 M solution) (4 mL). The reaction mixture was refluxed for 4 hours, and then cooled to room temperature. The mixture was partioned between chloroform (150 mL) and water (150 mL). The combined organic layer was dried with magnesium <n="92"/>sulfate. The residue was chromatographed on silica gel using a ethyl acetate/MeOH (20: 1) as an eluent to yield the final product 62 mg (yield 12%). MS (ESI) m/z 535.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 1h;Microwave irradiation; | Example 15; {3-[2-(4-Fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}- dimethyl-amine; 2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1 ,3,4]thiadiazole (0.13 g, 0.36 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (42 mg,0.036 mmol), <strong>[178752-79-9]3-(N,N-dimethylamino)phenylboronic acid</strong> (68 mg, 0.41 mmol), cesium carbonate (235 mg, 0.72 mmol, 2.0 eq), and water (1.5 mL) were added.The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140C for 1 hour. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage/Flash, silica, methanol:dichloromethane 0.2:9.8 to2:8). The obtained residue was crystallized from methanol: 1,2-dichloroethane(1 :1, 1.5 mL) and filtered to give {3-[2-(4-fluoro-phenoxy)-imidazo[2,1- b][1 ,3,4]thiadiazol-5-yl]-phenyl}-dimethyl-amine as a white solid (13 mg, 10% yield).1H-NMR (300 MHz, CDCI3) delta 7.51 (s, 1H), 7.37 (m, 2H), 7.29 (m, 2H), 7.16 (m,3H), 6.75 (d, J = 8.2 Hz, 1 H), 2.94 (s, 6H).MS (ES+) m/z 355 (M+H)+ (MW: 354.41). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 1h;Microwave irradiation; | Example 20; {5-[3-Dimethylamino-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-(4- methoxyphenyl)amine; (5-lodo-imidazo[2,1-b][1 ,3,4]thiadiazol-2-yl)-(4-methoxyphenyl)amine (55 mg, 0.10 mmol) was suspended in 1 ,4-dioxane (1 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (0.011 mmol, 12 mg), <strong>[178752-79-9]3-(N,N-dimethylamino)phenylboronic acid</strong> (0.202 mmol, 33 mg), cesium carbonate (0.268 mmol, 88 mg) and water (1 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140C for 1 hour. On cooling, the mixture was diluted with dichloromethane, adsorbed in silica and purified by column chromatography (Biotage/Flash, silica, methanokdichloromethane 0.2:9.8 to 2:8). The obtained residue was further purified by preparative HPLC to give {5-[3- dimethylaminophenyl)-imidazo[2, 1 -b][1 ,3,4]thiadiazol-2-yl]-(4-methoxyphenyl)- amine as a white solid (4 mg, 7% yield).1H-NMR (300 MHz, DMSOd6): delta 8.43 (br s, 1 H), 7.60 - 7.54 (m, 2H), 7.54 - 7.52 (s, 1 H), 7.52 - 7.49 (m, 1 H), 7.25 (t, J = 7.9, 1 H), 7.14 (d, J = 7.8, 1 H), 6.94 (d, J = 9.0, 2H), 6.67 (dd, J = 2.2, 8.0, 1 H), 3.75 (s, 3H), 2.99 (s, 6H). <n="68"/>MS (ES+) m/z 366 (M+H)+ (MW: 365.46). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With caesium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; at 140℃; for 0.333333h;Microwave irradiation; | In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-dif luoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol), 3-dimethylaminophenyl boronic acid (60 mg, 0.30 mmol), CS2CO3 (129 mg, 0.40 mmol), Pd(PPh3)2Cl2(7 mg, 0.01 mmol), dimethoxyethane (0.8 mL) , ethanol (0.2 mL), and a magnetic stir bar . The mixture was stirred at 140 C for 20 minutes under microwave irradiation, acidified with 3N HCl, and extracted twice with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was triturated with ether to give title compound (10 mg, 16 %).<ioo9> 1H NMROOOMHz, DMSO-cfe) : 59.48 (s, IH), 8.80(d, IH, J = 8.4 Hz), 8.66(s, IH), 7.63 ~ 7.50 (111, 2H), 7.37 ~ 7.20 (m, 3H), 6.92 (d, IH, J - 7.2 Hz), 5.20 - 5.11 (m, IH), 3.04 (s, 3Ii), 2.98 (s, 6H), 1.51 (d, 3H, J = 7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine;copper diacetate; In dichloromethane; at 20℃; for 72h;Molecular sieve; Inert atmosphere; | Example 31 (R)-1-(2-Benzylpiperazin-1-yl)-3-(2-(3-(dimethylamino)phenoxy)phenyl)propan-1-one The title compound was prepared as described in Scheme 9. Specifically, (R)-tert-butyl 3-benzyl-4-(3-(2-hydroxyphenyl)propanoyl)piperazine-1-carboxylate (prepared in Example 25) (150 mg, 0.35 mmol) were dissolved in dichloromethane (2 mL) and 4 A molecular sieves were added (200 mg). To the mixture was added copper acetate (320 mg, 1.76 mmol) and pyridine (0.2 mL, 1.76 mmol). The solution was stirred at room temperature for 72 h and the reaction mixture was diluted with dichloromethane (50 mL), filtered through celite, then washed with water (25 mL) and brine (25 mL). The organic layer was dried and concentrated in vacuo to an oil. This was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) was added. After 1 h of stirring at room temperature the reaction mixture was concentrated and the residue was purified by HPLC (30-60% acetonitrile in water, TFA buffered) to afford the title compound as a white semisolid (35.3 mg, 23%). ESI-MS: m/z 444.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; for 96h; | Intermediate tR [3-(5-lodo-imidazo[2,1 -b][1 ,3,4]thiadiazol-2-y l)-phenyl]-dimethyl-amineA mixture of 2-bromo-5-iodoimidazo[2,1-b][1 ,3,4]thiadiazole (0.150 g, 0.455 mmol, 1 eq), <strong>[178752-79-9]3-(N,N-dimethylamino)phenylboronic acid</strong> (0.113g, 0.682 mmol, 1.5 eq), Cs2CO3 (0.296 g, 0.909 mmol, 2 eq) and Pd(PPh3)4 (0.032 g, 0.027 mmol, 0.06 eq) were dissolved in Dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 95 ºC for 24 h. Additional amounts of 3-(N1N- dimethylamino)phenylboronic acid (1.5 eq) and Pd(PPh3)4 (0.06 eq) were added and the reaction mixture was heated at 95 ºC for 3 days. The solvent was removed in vacuo, redissolved in DCM/water (150 mL) and extracted with DCM (2 x 80 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (20-70% EtOAc in cyclohexane) to afford the desired product (36 mg, 21%) as a yellow solid. HPLC-MS (10-95% B in 4 min at 0.5 mL + 2 min 100% B, flow 0.8 mL/min, 5OºC): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 86℃;Inert atmosphere; | To a mixture of N-(4-bromo-3-methoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide ( 200 mg, 0.489 mmol), 3-dimethylaminophenyl boronic acid (100 mg, 0.61 mmol) in H2O/dioxane (0.2/8 ml) was added K2CO3 (200 mg, 1.45 mmol), followed by addition of [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium.CH2Cl2 (26 mg, 0.032 mmol). The resulting mixture was stirred at 86 0C under nitrogen overnight. The reaction mixture was dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction mixture was purified on silica gel eluting with 10-90% EtOAc/hexane to give the title compound as a solid (140 mg, 64%). 1H NMR (CDCl3) delta 8.54 ( d, 2H, J = 4 Hz), 7.37 (d, 2H, J = 8 Hz), 7.12 (d, IH, J = 8 Hz), 6.72 (d, IH, J = 8 Hz), 6.69-6.54 (m, 4H), 5.42 (bs, IH), 3.75 (ds, 6H), 3.68 (s, 3H), 3.45 (t, 2H, J = 8 Hz), 3.42 (s, 2H), 2.90 (s, 6H), 2.73 (t, 2H, J = 8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
106 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; benzene; for 24h;Reflux; Inert atmosphere; | The mixer containing 2 (95 mg), 3-dimethylaminophenylboronic acid (62 mg, 1.0 eq), Pd(PPh3)4 (10 mg, 0.02 eq) and Na2CO3 (320 mg, 8.0 eq) in 8 mL of H2O: EtOH: Benzene (v/v 3:3:10) was refluxed for 24 hrs under argon atmosphere. The reaction mixture was poured into H2O and extracted with CH2Cl2. The crude product after evaporation was purified by flash column using CH2Cl2 to yield NO550 (106 mg, 99%). 1HNMR (400 MHz, CDCl3) delta 8.13 (d, 1H, J=8.8 Hz), 7.89 (dd, 1H, J=7.2, 1.2 Hz), 7.73 (dd, 1H, J=8.4, 1.2 Hz), 7.54 (d, 1H, J=8.4 Hz), 7.50 (dd, 1H, J=8.8, 7.2 Hz), 7.38 (dd, 1H, J=7.6, 7.6 Hz), 7.26 (s, 1H), 6.84-6.77 (m, 3H), 4.48 (s, 2H), 3.008 (s, 6H). 13CNMR (400 MHz, CDCl3) delta 151.7, 140.5, 140.2, 133.4, 133.0, 132.1, 130.5, 127.3, 125.4, 124.5, 123.9. 118.9, 118.0, 115.8, 113.9, 112.4, 111.1, 41.2. HRMS m/z=288.1500 (M+H|), calculated 288.1495. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With triethylamine;copper diacetate; In dichloromethane; for 72h;Molecular sieve; under air; | A mixture of 2-chloro-3-fluoro-5-hydroxypyridine (2.0 gm, 0.0136 mol), <strong>[178752-79-9]3-(N,N-dimethylamino)phenylboronic acid</strong> (2.24 gm, 0.0136 mol), copper(II)acetate (2.7 gm, 0.0136 mmol), triethylamine (3.8 mL, 0.0272 mol) and powdered 4 molecular sieves in dichloromethane (100 mL) was stirred under air for 3 days. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluting with ethyl acetate:hexane (3:7) to afford [3-(6-Chloro-5-fluoropyridin-3-yloxy)phenyl]-dimethylamine as colourless oil (0.71g, 20%).ES+ 267 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With triethylamine;copper diacetate; In dichloromethane; for 72h;Molecular sieve; under air; | A mixture of 2-chloro-5-hydroxypyridine (3.0 gm, 0.023 mol), 3-(N,N-dimethylamino)-phenylboronic acid (5.73 gm, 0.034 mol), copper(II)acetate (4.62 gm, 0.023 mmol), triethylamine (16.0 mL, 0.115 mol) and powdered 4 A molecular sieves in dichloromethane (80 mL) was stirred under air for 3 days. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluding with ethyl acetate: hexane 3:7 to afford [3-(6-chloropyridin-3-yloxy)phenyl]-dimethylamine as a colourless oil (1.7 g, 29%). ES+ 249 (M+H)+ deltaH (d6-DMSO) 2.90 (3H, s), 6.30 (1H, dd), 6.44 (1H, dd), 6.57 (1H, dd), 7.21 (1H, t), 7.46 (1H, dd), 7.50 (1H, d) and 8.18 (1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Example 101 N-({2-[3-(dimethylamino)phenyl]-6-hydroxy-5-quinoxalinyl}carbonyl)glycine To a mixture of the compound from example 5(a) (0.300 g, 0.85 mmol), 3-(dimethylamino)phenylboronic acid (0.168 g, 1.02 mmol) and potassium carbonate (0.234 g, 1.69 mmol) in 1,4-dioxane (3.0 mL) and water (1.0 mL) was added tetrakis(triphenylphosphine)palladium (0.010 g, 8.47 mumol) followed by evacuation of the reaction vessel and purging with nitrogen. The reaction mixture was heated in a Biotage Initiator microwave synthesizer at 120 C. for 30 min to get intermediate ester and upon cooling, tetrahydrofuran (8.0 mL) and 1N aqueous sodium hydroxide (10.0 mL) were added. After stirring for 15 min at ambient temperature, the mixture was quenched with 1N aqueous hydrochloric acid and the resulting precipitate was filtered, washed through with methanol (20.0 mL) to afford the title compound (0.158 g, 51.0% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) delta ppm 15.20 (s, 1H, br), 12.92 (s, 1H, br), 11.41 (t, 1H, J=4.8 Hz), 9.50 (s, 1H), 7.55 (d, 3H, J=9.3 Hz), 7.39 (t, 1H, J=8.1 Hz), 6.92 (m, 1H), 4.26 (d, 2H, J=5.1 Hz), 3.02 (s, 6H). MS (ES+) m/e 367 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 80℃; for 5h;Inert atmosphere; | General Procedure: The appropriate organoboron compound (0.24 mmol), powdered K2CO3 (40 mg, 0.29 mmol), and 14 (100 mg, 0.20 mmol) were added to a sealed tube that had been purged with argon. A solution of Pd(PPh3)4 (10 mg) in degassed dioxane (1 mL) was added, and the reaction mixture was stirred under argon at 80 C for 5 h. The reaction mixture was cooled and filtered through a short celite pad. The filtrate was concentrated under reduced pressure to remove the solvents. The crude product was purified by flash chromatography (silica gel: 1.5-2.5% MeOH in CH2Cl2) to give compounds 15-30 (35.4-77.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper diacetate; triethylamine; In dichloromethane; | Intermediate 32: 2-Chloro-5-( -N,N-dimethylaminophenoxy)pyrimidineA mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (l.Og, 0.00766mol), 3-N,N- dimethylamino-phenyl boronic acid (1.26g, 0.00766mol), copper (II) acetate (1.39g, 0.00766mol), triethylamine (5.34mL, 0.00766mol) and powdered 4A molecular sieves in dichloro-methane (30mL) 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 flash chromatography using 0-15percent ethyl acetate: hexane as eluent to obtained 2-chloro-5-(3-N,N-dimethylaminophenyl)pyrimidine (0.448, 25percent) as a yellow oil.Mass: (ES+) 250 (M+H)+ HPLC: 99.8percentNMR: 5H (CDC13) 2.98 (6H, s), 6.35 (1H, dd), 6.40 (1H, m), 6.60 (1H, dd), 7.25 (1H, t) and 8.38 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 14h;Inert atmosphere; | General procedure: A mixture of aryl bromide (1 eq), substituted phenyl boronic acid (1.2 eq), sodium carbonate (2 eq) and tetrakis(triphenylphosphine) palladium (0.1 eq) in an oxygen free DME/water (1:1) solution was stirred at 80 C for 4-14 h under nitrogen. The reaction mixture was cooled to rt. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The product was purified by FC with n-hexane/ethyl acetate (6:1-3:1) as eluant. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate;palladium diacetate; XPhos; In water; acetonitrile; at 100℃; for 2h; | Example 64 - Preparation of Compound A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with l-(4-i-butylphenyl)naphthalen-6-yltrifluoromethanesulfonate (55 mg, 0.135 mmol), 3-(dimethylamino)phenylboronic acid (27 mg, 0.16 mmol), water/acetonitrile (1 mL/3 ml), K2CO3 (40 mg, 0.27 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (7 mg, 0.014 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)2 ( 2.0 mg, 0.007 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100 C and stirred for 2 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCCfe (15 mL), brine (15 mL), dried over NaiSCU. The organic layer was concentrated in rotavapor and purified on silica gel. Elution with 5% EtOAc/hexanes afforded the desired compound (30 mg, 59%) as a white solid. NMR (CDCls, 400 MHz) delta 8.02 (d, 1H, / = 1.60 Hz), 7.94 (d, 1H, / = 8.68 Hz), 7.82 (d, 1H, / = 8.20 Hz), 7.62 (dd, 1H, / = 1.64, 8.76 Hz), 7.26- 7.48 (m, 7H), 6.98-7.01 (m, 2H), 6.71 (dd,lH, / = 2.48, 8.28 Hz), 2.96 (s, 6H), 1.35 (s, 9H). |
59% | With palladium diacetate; potassium carbonate; XPhos; In water; acetonitrile;Inert atmosphere; | A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 1-(4-t-butylphenyl)naphthalen-6-yl trifluoromethanesulfonate (55 mg, 0.135 mmol), 3-(dimethylamino)phenylboronic acid (27 mg, 0.16 mmol), water/acetonitrile (1 mL/3 mL), K2CO3 (40 mg, 0.27 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (7 mg, 0.014 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)2 ( 2.0 mg, 0.007 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100 oC and stirred for 2 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 (15 mL), brine (15 mL), dried over Na2SO4. The organic layer was concentrated under reduced pressure and purified on silica gel. Elution with 5% EtOAc/hexanes afforded the desired compound (30 mg, 59%) as a white solid. 1H NMR (CDCl3, 400 MHz) delta 8.02 (d, 1H, J = 1.60 Hz), 7.94 (d, 1H, J = 8.68 Hz), 7.82 (d, 1H, J = 8.20 Hz), 7.62 (dd, 1H, J = 1.64, 8.76 Hz), 7.26-7.48 (m, 7H), 6.98-7.01 (m, 2H), 6.71 (dd,1H, J = 2.48, 8.28 Hz), 2.96 (s, 6H), 1.35 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate;palladium diacetate; XPhos; In water; acetonitrile; at 100℃; for 1.5h; | Example 66 - Preparation of Com oundA 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with the triflate (25 mg, 0.06 mmol), 3-(dimethylamino)phenylboronic acid (14 mg, 0.07 mmol), water/acetonitrile (1 mL/3 ml), K2CO3 (17 mg, 0.12 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5 mg, 0.01 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)2 ( 2.0 mg, 0.009 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100 C and stirred for 1.5 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCCb (10 mL), brine (10 mL), dried over Na2S04. The organic layer was concentrated with a rotavapor and purified on silica gel. Elution with 5% EtOAc/hexanes afforded the desired compound (16 mg, 67%) as a white solid. NMR (CDCI3, 400 MHz) delta 8.03 (d, 2H, / = 1.52 Hz), 7.94 (d, 1H, / = 8.80 Hz), 7.86 (d, 1H, / = 8.20 Hz), 7.58-7.70 (m, 5H), 7.25-7.52 (m, 8H), 7.67-7.01 (m, 2H), 6.69-6.72 (m, 1H), 2.95 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate;palladium diacetate; XPhos; In water; acetonitrile; at 100℃; for 1h; | Example 73 - Preparation of Compound A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with l-(4-fluorophenyl)naphthalene-6-yltrifluoromethanesulfonate ( 40 mg, 0.11 mmol), 3-(dimethylamino)phenylboronic acid (30 mg, 0.18 mmol), water/acetonitrile (1 mL/3 ml), K2CO3 (30 mg, 0.27 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.011 mmol). The resulting solution was degassed for 5 mi , then Pd(OAc)2 ( 2.0 mg, 0.006 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100 C and stirred for 1 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCOa (10 mL), brine (10 mL), dried over Na2S04. The organic layer was concentrated on a rotavapor and purified on silica gel. Elution with 5% EtOAc/hexanes afforded the desired compound (30 mg, 82%) as a white solid. NMR (CDCls, 400 MHz) delta 8.03 (d, 1H, / = 1.56 Hz), 7.80-7.86 (m, 2H), 7.64 (dd, 1H, / = 1.88, 8.84 Hz), 7.39-7.48 (m, 3H), 7.27-7.32 (m, 2H), 7.10-7.18 (m, 2H), 6.97-7.01 (m, 2H), 6.71 (dd, 1H, / = 2.56, 8.28 Hz), 2.30 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate;palladium diacetate; XPhos; In water; acetonitrile; at 100℃; for 1h; | C. Preparation of compound A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with l-(3-(benzyloxy)phenyl)naphthalen-6-yl trifluoromethanesulfonate (195 mg, 0.12 mmol), 4-(dimethylamino)phenylboronic acid (84 mg, 0.51 mmol), water/acetonitrile (1 mL/4 ml), K2CO3 (200 mg, 1.44 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (20 mg, 0.04 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)2 ( 5.0 mg, 0.02 mmol) was added and the solution was carefully degassed. The reaction mixture was heated to 100 C and stirred for 1 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCOa (15mL), brine (15 mL), dried over Na2SO4, concentrated on a rotavapor and purified on silica gel. Elution with 5% EtOAc/hexanes afforded the desired compound (168 mg, 92%) as a white solid. NMR (CDCls, 400 MHz) delta 8.02 (s, 1H), 7.87 (d, 1H, / = 8.92 Hz), 7.84 (d, 1H, / = 8.52 Hz), 7.61 (d, 1H, / = 8.76 Hz), 7.24-7.48 (m, 9H), 6.99-7.08 (m, 5H), 6.71 (1H, d, / = 8.16 Hz), 5.06 (s, 2H), 2.97 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;palladium diacetate; XPhos; In water; acetonitrile; at 100℃; for 1h; | Example 81 - Preparation of Compound A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with the starting material the triflate (16 mg, 0.03 mmol), 3- (dimethylamino)phenylboronic acid (7 mg, 0.45 mmol), water/acetonitrile (1 mL/3 ml), K2CO3 (20 mg, 0.14 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.012 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)2 ( 2.0 mg, 0.009 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100 C and stirred for 1 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCCh (10 mL), brine (10 mL), dried over Na2S0 . The organic layer was concentrated in rotavapor and purified on silica gel. Elution with 5% EtOAc/hexanes afforded a mixture (10 mg, -90% pure) of the desired compound and some impurity. The mixture was used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With potassium carbonate;palladium diacetate; XPhos; In water; acetonitrile; at 100℃; for 1.5h; | Example 92 - Preparation of Compound 5-([l,l'-Biphenyl]-4-yl)naphthalen-2-yl trifluoromethanesulfonate (24 mg, 0.056mM) was combined with (3-(dimethylamino)phenyl)boronic acid (18. 5 mg, 0.112 mM), K2CO3 (3 mg, 0.18 mM), and XPhos (3 mg, 0.006 mM). All this was dissolved in a solution consisting of 6mL of acetonitrile and 2 mL H2O. The mixture was then brought to 100 C. Pd(OAc)2 (10 mg, 0.046 mM) was then added and mixture was allowed to stir for 1.5 hours. After cooling to room temperature, crude reaction mixture was diluted with 50 mL of EtOAc and then filtered through a plug containing Celite and silica gel. Contents were then dried using a2S04 followed by vacuum concentration. Final product (5.4 mg, 24% yield) was afforded as a white solid using flash chromatography (10%EtOAc/hexanes). NMR (400MHz, CDCb) d = 3.03(s, 6H), 6.78(dd, /=2.32Hz, /=8.28Hz, 1H), 7.04-7.10(m, 1H), 7.33-7.41(m, 2H), 7.45-7.52(m, 3H), 7.56(t, /=7.20Hz, 2H), 7.61(d, /=8.20Hz, 2H), 7.68-7.75(m, 5H), 7.93(d, /=8.16Hz, 1H), 8.04(d, /=8.84Hz, 1H), 8.11(d, /=1.72Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate;palladium diacetate; XPhos; In water; acetonitrile; at 100℃; for 24h; | Example 96 - Preparation of Compound 5-(4-(Trifluoromethyl)phenyl)naphthalen-2-yl trifluoromethanesulfonate (98 mg, 0.233 mM) was combined with (3-(dimethylamino)phenyl)boronic acid (77 mg, 0.466 mM), K2CO3 (81 mg, .583 mM), and XPhos (11 mg, 0.0233 mM). All this was dissolved in a solution consisting of 5 mL of acetonitrile and 3 mL H2O. The mixture was then brought to 100 C. Pd(OAc)2 (5 mg, 0.222 mM) was then added and mixture was allowed to stir for 24 hours. After cooling to room temperature, crude reaction mixture was diluted with 50 mL of EtOAc and then filtered through a plug containing Celite and silica gel. Contents were then dried using Na2S04 followed by vacuumconcentration. Final product (74 mg, 81% yield) was afforded as a white solid using flash chromatography (10%EtOAc/hexanes). NMR (400MHz, CDCls) d = 2.92(s, 6H), 6.70(dd, J=2.32Hz, /=8.28Hz, 1H), 6.95(m, 2H), 7.27(m, 2H), 7.44(t, /=7.28Hz, 1H), 7.54(d, /=8.06Hz, 2H), 7.63(dd, J=1.9Hz, /=8.84Hz, 1H), 7.67(d, /=8.16Hz, 2H), 7.77(d, /=8.8Hz, 1H), 7.85(d, /=8.2Hz, 1H), 8.01(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); cesium fluoride; In methanol; 1,2-dimethoxyethane; at 20 - 110℃; under 1500.15 Torr; for 0.65h;Inert atmosphere; Microwave irradiation; | General procedure: To a solution of 3-substituted-2-iodo imidazo[4,5-b] pyridine derivative (1 equiv) in dimethoxyethane/MeOH (4:1), was added (A-taphos)2PdCl2 (5mol%). The solution was purged with nitrogen and stirred at room temperature for 0.15 h, at which time the boronic acid (1.8equiv), and cesium fluoride (2 equiv) were added. The reaction solution was purged again with nitrogen and then placed in the microwave and heated for 10 to 30 mts at 110 C. When TLC and LCMS showed full consumption of starting materials, the reaction mixture was diluted with ethyl acetate, separated the ethyl acetate layer, given water wash, brine wash and was dried over anhydrous sodium sulphate and concentrated to get the crude material. The crude product was directly purified by column chromatography (0-20% hexane/EtOAc) to isolate the 3-substituted-2-aryl/heteroarylimidao[4,5-b] pyridine derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 95℃; for 24h;Inert atmosphere; | General procedure: To an array of vials containing a solution of aryl triflate 10 (30 mg, 1 equiv) in 1,4-dioxane (1 mL)was added various aryl boronic acids (1.1 equiv), [1,10-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.03 equiv) and aqueous K3PO4 (3 equiv). The reaction mixtures were degassed with nitrogen and heated at 95 C for 24 h. The reaction mixtures were cooled to room temperature and were filtered through a short pad of silica. The filtrates were evaporated in a Genevac. To the resulting array of crude aldehyde was added a suspension of sodium borohydride (1 equiv) in anhydrous ethanol (1 mL). The reaction mixtures were stirred at room temperature for 4 h. The solvents were evaporated in a Genevac and the residues were purified by reverse phase preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;Inert atmosphere; | General procedure: Under a nitrogen atmosphere, to a mixture of compound 13 (1 g, 2 mmol, 1 eq), 3,4 - methylenedioxyphenyl boronic acid (0.4 g , 2.46 mmol, 1.2 eq) in DMF (5 mL) was added palladium (0) tetrakis(triphenylphosphine) (0.162 g, 0.14 mmol 0.07 eq). The mixture was stirred at 60 oC for 8 h, diluted with EtOAc, and quenched with saturated NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by normal phase column (EtOAc in hexane 25%-50%) to yield the desired product (0.92 g, 1.7mmol, 86% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With potassium phosphate;palladium diacetate; XPhos; In 1,4-dioxane; at 90℃; | Step 2: (S)-6-(3-(dimethylamino)phenyl)-4-(l -hydroxy -4-methylpentan-2-ylamino) pyrr -b]pyridazine-3 -carboxamide.[00282] A mixture of (S)-6-bromo-4-(l-hydroxy-4-methylpentan-2-ylamino) pyrrolo [l,2-b]pyridazine-3 -carboxamide (23 mg, 0.070 mmol), 3-(N,N- dimethylamino)phenyl boronic acid (16 mg, 0.1 mmol), palladium (II) acetate (1.46 mg, 0.0065 mmol), potassium phosphate, tribasic, 2M (0.1 mL, 0.2 mmol) and 2- (dicyclohexylphosphino)-2',4',6'-triisopropylbyphenyl (6.2 mg, 0.013 mmol) in dioxane (Volume: 0.65 mL) was heated to 90 C overnight. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.8 mg, 15% yield). MS (ES+) m/z: 396.1 (M+H); LC retention time: 1.83 min (analytical HPLC Method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; benzene; at 85℃;Inert atmosphere; | (i) Preparation of 21b: (4aS,6aS,6bR,12aR)-benzyl 11-cyano-14-(3-(dimethylamino)phenyl)-2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4-a-carboxylate To a mixture of IIj (300 mg, 0.46 mmol) and 3-(dimethylamino)phenylboronic acid (458 mg, 2.78 mmol) in benzene (10 mL) and EtOH (5 mL) was added K2CO3 (511 mg, 3.70 mmol). The mixture was sparged with nitrogen and then Pd(PPh3)4 (107 mg, 0.09 mmol) was added. The mixture was heated at 85 C. overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the solution was washed with brine then dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-10% EtOAc in hexanes) to afford the sub-title compound (270 mg, 84%). 1H NMR (300 MHz, CDCl3) delta 0.29-2.30 (m, 41H), 2.95 (s, 6H), 3.13 (d, J=10.5 Hz, 1H), 3.81-3.91 (m, 1H), 5.07 (d, J=12.3 Hz, 1H), 5.17 (d, J=15.3 Hz, 1H), 6.51 (d, J=6.9 Hz, 1H), 6.51 (d, J=6.9 Hz, 1H), 7.03-7.09 (m, 1H), 7.34-7.36 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; N,N-dimethyl-formamide; at 110℃; for 0.5h;microwave irradiation;Product distribution / selectivity; | Alternatively, 3 reactions were set up and the experimental procedures were as follows: A mixture of 1 ,1 -dimethylethyl 4-(3-bromo-4-[(3-chlorophenyl)sulfonyl]amino}-6- methylthieno[2,3-6]pyridin-2-yl)-1 /-/-pyrazole-1 -carboxylate (Description 75) (100 mg, 0.171 mmol), 3-(/V,/V-dimethylamino)-phenylboronic acid (56.5 mg, 0.343 mmol), potassium carbonate (71.0 mg, 0.514 mmol) andtetrakis(triphenylphosphine)palladium(0) (4.95 mg, 4.28 muetaetaomicronIota) were weighed into a microwave vial. 1 ,4-Dioxane (1.5 mL), DMF (0.75 mL) and water (0.38 mL) were added and the mixture heated in a microwave at 1 10C for 30 min. At this point, the three reaction mixture were combined and concentrated. The residue was passed through an SCX cartridge, eluted with MeOH (100 mL) and then with 2M NH3 in MeOH (120 mL). The basic methanolic solution was concentrated and the residue purified by MDAP (acidic conditions), to give the title compound (95.6 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 1h;Microwave irradiation; | General procedure: <strong>[290368-00-2]ter<strong>[290368-00-2]t-butyl 3-iodo-1H-indazole-1-carboxylate</strong></strong> (S2, 100 mg, 0.29 mmol) was placed in a microwave vial and dissolved in 1,4-dioxane (11.5 mL). 3-Methoxyphenylboronic acid (88 mg, 0.58 mmol, 2.0 equiv) and tetrakis(triphenylphosphine)palladium (20 mg, 0.017 mmol, 0.06 equiv) were added, and the resulting mixture was sparged thoroughly with nitrogen. An aqueous solution of sodium carbonate (2.0 M, 0.65 mL, 1.3 mmol, 4.5 equiv) was then added. The biphasic mixture was microwaved for 1 hour at a reaction temperature of 120 C. After cooling to room temperature, the reaction was diluted with ethyl acetate (2 mL), and then filtered through a celite pad with additional ethyl acetate. The filtrate was concentrated under reduced pressure to give an oil. The crude material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 30/70) to give the title compound as an oil (58.0 mg, 89%). |
Tags: 178752-79-9 synthesis path| 178752-79-9 SDS| 178752-79-9 COA| 178752-79-9 purity| 178752-79-9 application| 178752-79-9 NMR| 178752-79-9 COA| 178752-79-9 structure
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