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CAS No. : | 458532-96-2 | MDL No. : | MFCD03788416 |
Formula : | C5H5BClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WJYRVVDXJMJLTN-UHFFFAOYSA-N |
M.W : | 157.36 | Pubchem ID : | 5151595 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 39.07 |
TPSA : | 53.35 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) : | -6.75 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.72 |
Log Po/w (WLOGP) : | -0.59 |
Log Po/w (MLOGP) : | -0.75 |
Log Po/w (SILICOS-IT) : | -0.5 |
Consensus Log Po/w : | -0.22 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.65 |
Solubility : | 3.55 mg/ml ; 0.0225 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.42 |
Solubility : | 6.0 mg/ml ; 0.0381 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.52 |
Solubility : | 4.77 mg/ml ; 0.0303 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.77 |
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 |
---|---|---|
47% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 0.333333 - 0.666667h;Microwave irradiation;Product distribution / selectivity; | EXAMPLE 73; 3-(2-Chloropyridin-4-ylV5,5-dimethyl-2-(morpholin-4-ylV5,6-dihydro-l-benzothiophen-; The title compound was prepared from Example 17 and 2-chloropyridin-4- ylboronic acid according to Method J and was isolated as an off-white solid (47%) after purification by preparative HPLC (pH 2.5). deltaH (DMSOd6) 8.50 (IH, s), 7.59 (IH, s), 7.49 (IH, d, J6.0 Hz), 3.64-3.58 (4H, m), 2.96-2.92 (4H, m), 2.54 (2H, s), 2.38 (2H, s), 0.97 (6H, s). LCMS (ES+) 377.3 (M+H)+.; EXAMPLE 89 (METHOD K); 5,5-Dimethyl-2-(morpholin-4-yl)-3-(2-phenylrhoyridin-4-yl')-5,6-dihvdro-l-benzothiophen-; To a stirred solution of Example 17 (0.150 g, 0.384 mmol), Pd(PPh3)4 (0.050 g, 0.040 mmol) and K3PO4 (0.100 g, 0.470 mmol) in a mixture of water (1 mL) and DME (3 mL) was added 2-chloropyridin-4-ylboronic acid (0.060 g, 0.384 mmol) and the reaction mixture was heated to 12O0C in a sealed tube, under microwave irradiation, for 20 minutes. Phenylboronic acid (0.060 g, 0.492 mmol) was then added and the reaction mixture was heated again to 12O0C in a sealed tube, under microwave irradiation, for 30 minutes. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (pH 2.5) to give the title compound (0.033 g, 21 %) as an off-white solid. deltaH(DMSO-d6) 8.75 (2H, d, J4.9 Hz), 8.15 (IH, d, J 6.8 Hz), 8.06 (IH, s), 7.60-7.40 (4H, m), 3.63 (4H, m), 3.01 (4H, m), 2.62 (2H, s), 2.42 (2H, s), 1.01 (6H, s). LCMS (ES+) 419.0 (M+H)+. |
27% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 0.333333h;Microwave irradiation; | INTERMEDIATE 72S-^-Chloropyridin^-vD-S^-dimethyl^-rmorpholin^-vD-S.-dihvdro-l-benzothiophen- 7(4HVone A mixture of Intermediate 71 (520 mg, 1.33 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (319 mg, 1.33 mmol), potassium phosphate tribasic (847 mg, 3.99 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in water (1 mL) and DME (3 mL) was heated at 12O0C under microwave irradiation for 20 minutes. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 0-60% EtOAc in heptane) to give the title compound (136 mg, 27%) as an off-white solid, delta? (DMSO-d6) 8.50 (s, 1eta), 7.59 (s, 1eta), 7.49 (d, J6.0 Hz, IH), 3.64-3.58 (m, 4H), 2.96-2.92 (m, 4H), 2.54 (s, 2H), 2.38 (s, 2H), 0.97 (s, 6H). LCMS (ES+) 377.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; for 6h;Heating / reflux; | EXAMPLE 7 Preparation of 1-[3-(2-Chloro-pyridin-4-yl)-phenyl]-ethanone 2-Chloropyridine-4-boronic acid (11.0 g, 69.9 mmol), 3-Bromoacetophenone (11.2 mL, 83.9 mmol, 1.2 eq.), Na2CO3 (35 mL, 244.65 mmol, 3.5 eq.) and dppfPdCl2 (572 mg, 0.07 mmol, 0.01 eq.) were mixed in THF (200 mL). The mixture was heated to reflux and continued at this temperature for 6 hours. It was then cooled and concentrated in vacuo. The residue was partitioned between DCM and water (100 mL/40 mL). The layers were separated and the aqueous layer was washed further with DCM (2×40 mL). The combined organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated, and the residue was chromatographed using 1/1 hexane/EtOAc to give 1-[3-(2-Chloro-pyridin-4-yl)-phenyl]-ethanone as a white solid (9.5 g, 58%). MS: m/z 232.1 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00726] Example 13: 4- [ (aminocarbonyl) amino]-1- [3- (2-chloropyridin-4- yl) phenyl]-1 H-pyrazole-3-carboxamide; [00728] <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (37.4 mg, 0.2 mmol), 4- [ (aminocarbonyl) amino]-1- (3-bromophenyl)-1 H-pyrazole-3-carboxamide (Example 20,78 mg, 0.24 mmol), and bis (triphenylphosphino) palladium dichloride (14 mg, 0.01 mmol) were sequentially added to degassed DMF (1 mL). The mixture was stirred at room temperature for 30 min. Degassed 2M aqueous cesium carbonate (0.3 mL) was added to the mixture, and the reaction mixture was heated to 95C overnight. The reaction was cooled to room temperature, filtered through a syringe filter (0.45 um), purified by prep. rpHPLC, and lyophilized to give the title compound as a white solid.'H NMR (300 MHz, DMSO-d6) : 5 6.51 (m, 2 H) 7.55 (m, 1 H) 7.65 (t, J = 7. 95 Hz, 1 H) 7.81 (d, J = 7. 85 Hz, 1 H) 7.90 (m, 2 H) 8.03 (m, 2 H) 8.35 (t, J = 1. 81 Hz, 1 H) 8.51 (d, J = 5.24 Hz, 1 H) 8.68 (s, 1 H) 8.76 (s, 1 H). Mass of molecular ion (M + H): 357.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 160℃; for 0.25h;Microwave irradiation; | A mixture of azaindole 3 (80 mg, 0.23 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (41 nag, 0.27 mmol), Pd(Ph3P)4 (20 mg, 0.11 mmol) and 2 M sodium carbonate (.34 mL, 0.68 mmol) in 2 mL of DME was microwave on high at 160C for under nitrogen for 15 minutes. Diluted with ethyl acetate and the organic phase washed with water and brine then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexanes) to give 60 mg (68%) of the desired product 14. 1H NMR CDCl3 8.6 (d, 2H), 8.1 (m, 4H), 7.25 (m, 5H), 2.5 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 200℃; for 0.166667h;Microwave irradiation; | Example 129 Preparation of 8-(4-chlorophenyl)-7-(3-chloropyridin-4-yl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (20 mg, 0.05 mmol), 2-chloro-4-pyridylboronic acid (31 mg, 0.20 mmol), and tetrakis(triphenylphosphine)palladium (3 mg, 0.002 mmol) in dioxane (0.4 mL) at 20 C. was added K2CO3 (30 mg, 0.2 mmol) in water (0.13 mL). The resulting reaction mixture was heated in a microwave reactor at 200 C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (5 mg, 0.011 mmol) as an off-white solid. MS: [M+H]+=446. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 80℃; for 3h; | 2-Chloropyridine-4-boronic acid (0.206 g, 0.86 mmol), methyl 5-(5-bromo-1 H- benzimidazol-1 -yl)~3-({(1 Zt)- 1 -[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene-2- carboxylate (0.226 g, 0.43 mmol), and sodium carbonate (1 N in water, 1.7 EPO <DP n="85"/>mL) were combined in /V.LambdaAdimethylacetamide (6 ml_). 1 ,1'- bisdiphenylphosphino-ferrocene dichloropalladium (II) (0.070 g, 0.086 mmol) was added and the reaction mixture was stirred under nitrogen while heating at 80 0C for 3 h. The mixture was then cooled and partitioned between 5:1 dichloromethane:methanol and saturated aqueous sodium bicarbonate. The organic layer was washed with twice with brine, dried over sodium sulfate, and concentrated onto Celite. Purification by column chromatography (10 to 100% 1/9/90 ammonium hydroxide/methanol/dichloromethane: dichloromethane) provided 0.105 g (44%) of the title compound as an off- white solid. 1H NMR (400 MHz, CDCI3): delta 8.43 (d, 1 H, J= 5.3 Hz), 8.04 (d, 2H, J= 13.9 Hz), 7.90 (d, 1 H, J= 7.9 Hz), 7.66 (d, 1 H, J= 7.9 Hz), 7.58 (m, 4H), 7.47 (dd, 1 H, J= 1.1 , 5.1 Hz), 7.41 (t, 1 H, J= 7.6 Hz), 6.78 (s, 1 H), 5.81 (q, 1 H, J= 6.2 Hz), 3.92 (s, 3H), 1.77 (d, 3H, J= 6.2 Hz); MS (ESI): 558.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 80℃; for 18.33h; | mixture of 3,6-dichloro-pyridazine (1.04 g, 6.98 mmol) and 2-chloropyridine boronic acid (1.00 g, 6.37 mmol) in 2.0 M potassium carbonate (10 mL, 20 mmol) and 1,4-dioxane (20 mL) was bubbled with argon for ~ 10 min, bis(triphenylphosphine) palladium (II) dichloride (236 mg, 0.336 mmol) was then added. After flushing with argon for another ~ 10 min, the mixture was heated at 80 0C for 18 h and allowed to cool to room temperature. The solid was removed by <n="153"/>filtration through Celite, and the filtrate; was separated. The aqueous solution was extracted with CH2CI2 and the combined organic phases were dried, concentrated, and purified by column to provide 296 mg (21%) of 100a as a solid: 1H NMR (400 MHz, CDCl3) 68.58 (d, J = 5.1 Hz, 1 H), 8.00 (m, 1 H), 7.90 (dd, J = 5.5, 1.6 Hz, 1 H), 7.89 (d, J = 9.0 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 1 H); MS (ES) m/z: 226/228 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 80℃; for 2h;Microwave; | To a solution of 4-(3-bromo-imidazo{l,2-b]pyridazine-6-ylamino)cyclohexanol (1 eq, 8.7 mmol, 2.7 g), 3-chloropyrid-4-yl boronic acid (1.5 eq, 13 mmol, 2.05 g), Na2COs (2 eq, 17.4 mmol, 1.84 g) in dioxane (6.0 ml) and water (3 ml), under inert atmosphere is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.87 mmol, 609 mg). The reaction mixture is heated in a microwave at 80 0C for 2 hours. The mixture is diluted with H2O (50 EPO <DP n="52"/>ml) and extracted with EtOAc. The combined organic portions are washed with brine, then dried (MgSCM) and concentrated in vacuo. The residue is purified by silica chromatography eluting with 2-10% EtOAc in MeOH to afford the desired final compound, 4-[3-(2-chloro- pyridyl)-imidazo[l,2-b]pyridazin-6-ylamino]-cycloxhexanol; [M+H]+ 345, 347. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With pyridine;copper diacetate; In chloroform; at 35℃; for 18h; | Example 7 [6-Bromo-1-(2-chloro-pyridin-4-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone A suspension of 0.15 g (0.25 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 1), 119 mg (0.76 mmol) <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong>, 91 mg (0.50 mmol) copper(II) acetate and 80 muL (78 mg, 1.0 mmol) pyridine in 4 ml chloroform was stirred 18 h at 35 C. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant to afford 84 mg (47%) of the title compound as a light-yellow solid. MS (ISP): 707.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 120℃; | A mixture of compound 1AL (10 g, 20.66 mmol), compound 5AL (3.23 g, 20.66 mmol), Pd(PPh3)4 (2.3 g, 2 mmol) and 1 :1 dioxane/Na2CO3 (2M) (70 ml) was degassed for 15 min. Then it was heated at 120 C for overnight. Cooled down to room temperature and added compound 10AL (3.47 g, 20.66 mmol), then heated at 120 C for overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 120.0℃; for 0.166667h;Microwave radiation; | 3-Bromo-7-chloro-imidazo-[1,2-a]-pyridine (1 eq, 6.48 mmol, 1.5 g) and 2-chloro- pyridine-4-boronic acid (1 eq, 6.48 mmol, 1.02 g) are dissolved in DME (6 ml) and water (2 ml) and Na2CO3 (2 eq, 13.0 mmol, 1.61 g) is added. PdCl2(PPh3J2 (0.06 eq, 0.389 mmol, 273 mg) is added and the reaction mixture is heated using microwave radiation at 120C for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-chloro-3-(2-chloro-pyridin-4-yl)-imidazo[1,2- ajpyridine as an orange solid; [M+H]+ = 265 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 95℃; for 16h; | Step 2: [4-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol To a solution of 4-(3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (1 eq, 9.6 mmol, 3 g), 3-chloropyrid-4-yl boronic acid (1.05 eq, 10.1 mmol, 1.6 g), Na2COs (2 eq, 19 mmol, 2 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.96 mmol, 679 mg). The reaction mixture is heated at 95 C for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgStheta4) and concentrated in vacuo. The residue is purified <n="102"/>by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+ = 343/345 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 100.0℃; for 16.0h; | To a solution of <strong>[886371-28-4]3-bromo-6-chloro-imidazo[1,2-a]pyridine</strong> (1 eq, 18.1 mmol, 4.2 g), 2- chloropyridin-4-yl boronic acid (1.05 eq, 19 mmol, 3 g), Na2COs (2 eq, 36.2 mmol, 3.84 g) in dioxane (30 ml) and water (10 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (1.23 g). The reaction mixture is heated at 100 C for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgStheta4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound; [M+H]+ =264 (266). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 95℃; for 16h; | To a solution of 3-trans-RS/RS (3-bromo-imidazo[1,2-a]pyridin-6-ylamino)- cyclohexanol [intermediate J step 2] (leq, 13.7 mmol, 4.25g), 3-chloropyridin-4-yl boronic acid (1.05 eq, 15 mmol, 2.37 g), Na2COs (1 eq, 13.7 mmol, 1.4g) in dioxane (125 ml) and water (22 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 560 mg). The reaction mixture is heated at 95 C for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgStheta4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+ = 343/345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 95℃; for 16h; | To a solution of 3-Bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine (leq, 2.9 mmol, 0.77 g), 2-chloropyrid-4-yl boronic acid (1.05 eq, 3.05 mmol, 0.478 g), Na2CO3 (2 eq, 5.81 mmol, 0.616 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.03 mmol, 200 mg). The reaction mixture is heated at 95 C for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgStheta4) and concentrated in vacuo. The residue <n="123"/>is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+ = 297/299 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 95℃; for 16.0h; | To a solution of 3-Bromo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (leq, 23 mmol, 5.9 g), 2-chloropyrid-4-yl boronic acid (1.05 eq, 24 mmol, 3.8 g), Na2COs (2 eq, 46 mmol, 4.9 g) in dioxane (40 ml) and water (15 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 2.4 mmol, 1.6 g). The reaction mixture is heated at 95 C for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions <n="124"/>are washed with brine, dried (MgStheta4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+ = 287/289. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 95℃; for 16h; | To a solution of (lSR,3RS)-3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylamino)- cyclohexanol (leq, 1 mmol, 0.34g), 3-chloropyridin-4-yl boronic acid (1.05 eq, 1.05 mmol, 0.29 g), Na2COs (2 eq, 1.9 mmol, 0.2 g) in dioxane (5 ml) and water (1 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 70 mg). The reaction mixture is heated at 95 C for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic <n="126"/>portions are washed with brine, dried (MgSCU) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+ = 343/345 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In tetrahydrofuran; water; at 70℃; for 2h;Inert atmosphere; | To a mixture of <strong>[77337-82-7]1-bromo-2-methoxy-4-nitrobenzene</strong> (1.00 g, 4.31 mmol) and 2-chloropyridin-4-ylboronic acid (1.02 g, 6.46 mmol) in THF (20 mL) was addedsodium carbonate (2M in H20) (6.46 mL, 12.93 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.151 g, 0.215 mmol) was added. N2 was bubbled for 2 mm. The reaction mixture was heated in at 70 C for 2 h. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (25 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL).The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (20% -* 50% ethyl acetate in hexanes; 40g column) to afford 2-chloro-4- (2-methoxy-4-nitrophenyl)pyridine (320 mg, 28% yield) as a colorless solid: ?H NMR (400MHz, DMSO-d6) oe 8.51 (d, J=5.5 Hz, 1H), 7.96 - 7.92 (m, 2H), 7.74 -7.70 (m, 2H), 7.61 (dd, J=5.0, 1.5 Hz, 1H), 3.95 (s, 3H); LC/MS (ESI) m/e 265.0 [(M+H), calcd for C,2H,0N203C1 265.0]. |
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; | Reference 3; Synthesis of 4-(2-chloropyridin-4-yl)-3-methoxyaniline Step 1 l-Bromo-2-methoxy-4-nitrobenzene (4.5 g, 0.019 mol; Alfa Asear), (2-chloropyridin- 4-yl)boronic acid (3.10 g, 0.0197 mol; Combi-Blocks), and tetrakis(triphenylphosphine)- palladium(O) (1.9 g, 0.0016 mol) were added to a flask and the flask purged with nitrogen. 1,2- Dimethoxyethane (150 mL, 1.4 mol) was added and the solution degassed. Cesium carbonate (19 g, 0.060 mol) was dissolved in water (70.6 mL, 3.92 mol) and this solution was added to the reaction mixture and the reaction mixture again degassed. The dark red slurry was heated to reflux (oil bath at 95 0C) and the solids were all in solution. The reaction mixture was heated at reflux for 18 hours and then cooled overnight and held at room temperature for the weekend. The volatiles were removed under vacuum and the resultant slurry was diluted with DCM and additional water and placed in a separatory funnel. The phases were separated and the water extracted two additional times with DCM. The DCM layers were combined, dried over Na2SO4 and concentrated to a brown-red solid. To this was added MTBE and the mixture was triturated and then the volume was reduced to yield a slurry. The slurry was cooled in an ice bath, filtered and rinsed with 1 : 1 MTBE/hexanes and then hexanes to yield 2-chloro-4-(2- methoxy-4-nitrophenyl)pyridine. The filtrate from the above crystallization was concentrated to a dark red solid (3.5 g) and loaded onto 6 g silica gel (DCM) and purified by column chromatography eluting with a 15-55% ethyl acetate/hexanes gradient to give additional product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With potassium phosphate; tetrabutylammomium bromide;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 24h; | INTERMEDIATE 573-(2-Chloropyridin-4-yl)-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno|'2,3- c1pyridin-7(4iy)-oneA mixture of Intermediate 56 (1.0 g, 2.55 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (0.41 g, 2.61 mmol), potassium phosphate (0.55 g, 2.59 mmol) and tetra-n-butyl- ammonium bromide (0.82 g, 2.55 mmol) in DME (30 mL) and water (9 mL) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 2.60 mmol) was added and the reaction mixture was heated to 9O0C for 24 h. Sat. NaHCO3 solution was added and the mixture was extracted with EtOAc. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 30-75% EtOAc in heptane) to give the title compound (220 mg, 23%) as a cream solid, delta? (CD3OD) 8.41- 8.47 (m, IH), 7.44-7.70 (m, 3H), 3.69-3.77 (m, 4H), 2.94-3.02 (m, 4H), 2.75 (s, 3H), 1.32 (s, 6H). LCMS (ES+) 378.2, 380.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium phosphate; tricyclohexylphosphine;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 60℃;Inert atmosphere; | Example 4 Method G: 2-(2-chloropyridin-4-yl)-5,6,7,8-tetrahydro-7,7-dimethylthiazolo[5,4-c]azepin-4-one (I-4) 2-bromo-5,6,7,8-tetrahydro-6,6-dimethyl thiazolo[5,4-c]azepin-4-one (200 mg, 1.0 Eq.), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (126 mg, 1.1 Eq.), Pd2(DBA)3 (27 mg, 0.04 Eq.), K3PO4 (341 mg mg, 2.2 Eq.), were suspended/dissolved in H2O/dioxane (0.5 mL/2.5 mL) and degassed (vacuum/N2 cycles*5). Tricyclohexyl phosphine (20 mg, 0.1 Eq.) was then added, and the reaction mixture was 60 C. overnight. The reaction mixture was allowed to cool to RT, partitioned between EtOAc/H2O, and then filtered through celite. The aqueous layer was diluted with sat. Na2CO3 and extracted into EtOAc (3*50 mL). The combined organic layers were washed with brine (1*50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (100% EtOAc), followed by tritration in Et2O. The precipitate was then washed with pentane. The title compound was obtained as a light yellow solid (74.1 mg, 33% yield); 1H NMR (DMSO D6) 1.0 (6H, s), 3.0 (4H, m), 7.9 (1H, m), 8.0 (1H, s), 8.8 (1H, br m), 9.1 (1H, m); LC/MS M+1; (obs.) 308.1; LC/MS M-1 (obs.) 306.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 90℃;Inert atmosphere; | A mixture of 4-(6-bromopyridin-2-yl)-piperazine-1-carboxylic acid te/f-butyl ester (1.98 g, 5.78 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (1.0 g, 6.35 mmol), Pd(Ph3P)4 (0.330 g, 0.289 mmol), aqueous solution of Na2CO3 (5.7 ml_, 2.0 M) and CH3CN (10 ml.) is sparged with argon for 10 min. The vessel is then sealed and the contents heated to 90 0C for 4 h. The mixture is then allowed to cool followed by concentration. The residue is taken up in CH2CI2 and washed with H2O. The aqueous layer is further extracted with CH2CI2 (2 x 50 ml_). The combined organic layers are then dried (Na2SO4), filtered and concentrated. The residue is then separated via flash chromatography (SiO2, 20-30% EtOAc/hexanes gradient) to give the title compound 4-(2'-chloro-[2,4']bipyridinyl-6-yl)-piperazine-1-carboxylic acid te/f-butyl ester. MS (ESI) m/z 375.0, 376.9 (M+1 ). 1H NMR (400 MHz, CDCI3) delta ppm 8.44 (d, J=5.3 Hz, 1 H), 7.93 (s, 1 H), 7.78 (dd, J=5.1 , 1.5 Hz, 1 H), 7.61 (dd, J=8.5, 7.5 Hz, 1 H), 7.16 (d, J=7.3 Hz, 1 H), 6.73 (d, J=8.6 Hz, 1 H), 3.55 - 3.69 (m, 8 H), 1.50 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 80℃; for 4h; | Stirred 4-(6-bromo-4-methoxycarbonyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert- butyl ester (1.5 g, 3.76 mmol) and <strong>[458532-96-2]2-chloro-4-pyridine boronic acid</strong> (0.71 g, 4.51 mmol) in DME (25 ml_). To this is added 2.0 M Na2CO3 solution (6.0 mL, 1 1.28 mmol) and Pd(dppf)CI2.CH2CI2 (0.31 g, 0.37 mmol). This above suspension is heated to 80 0C for 4 h. Reaction is diluted with EtOAc (25 mL) and extracted between organic and saturated NaHCO3 (x2). The organic layer is washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to provide a crude residue that is purified via flash chromatography (SiO2, EtOAc/heptanes gradient) to afford the compound as a pale yellow solid (1.4O g, 87%). MS (ESI) m/z 433.2 (M+1 ). 1H-NMR (400 MHz, CD2CI2) delta ppm 8.37 (d, J=4.5 Hz, 1 H), 7.92 (d, J=1.5 Hz, 1 H), 7.79 (dd, J=5.1 , 1.5 Hz, 1 H), 7.60 (s, 1 H), 7.26 (s, 1 H), 3.86 (s, 3 H), 3.57 - 3.68 (m, 4 H), 3.41 - 3.53 (m, 4 H), 1.39 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | To a stirred solution of Int-1 (20.0 g, 212 mmol) in DME (100 mL) was added Int-2 (25 mL, 318 mmol) at room temperature. The reaction mixture was heated to 85 C. and then stirred for 24 hours. After reaction completion, the volatiles were concentrated under reduced pressure and the residue was diluted with saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water (50 mL), brine (2×75 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to get crude compound. The obtained crude material was purified by column chromatography using 1% MeOH/DCM to afford Int-3 (6.0 g, 21%). Mass (m/z): 133 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 8.05 (d, J=8.2 Hz, 1H), 7.35 (s, 1H), 7.1 (t, J=6.8 Hz, 1H), 6.7 (t, J=6.8 Hz, 1H), 6.5 (d, J=8.2 Hz, 1H), 2.45 (s, 3H). To a stirred solution of Int-3 (5.0 g, 37.8 mmol) in CH3CN (16 mL) was added NIS (10.2 g, 45.4 mmol) at room temperature and then stirred for 1 hour. After reaction completion, the volatiles were concentrated under reduced pressure and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under vacuum to afford Int-4 (4.5 g, 46%). Mass (m/z): 259 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 8.22 (d, J=8 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.29 (t, J=7.0 Hz, 1H), 2.35 (s, 3H). Int-4 (3.0 g, 11.62 mmol) was dissolved in iPrOH-H2O (50 mL, 1:1) and purged with N2 for 5 minutes. Then PdCl2 (dppf).DCM (1.89 g, 2.3 mmol) and t-BuNH2 (1.8 mL) were added to the reaction mixture at room temperature. After being stirred for 15 minutes, 2-chloro pyridine 4-boronic acid (1.47 g, 9.3 mmol) was added to the reaction mixture and heated at 100 C. for 16 hours. After completion, the volatiles were concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to get crude product. The obtained crude material was purified by column chromatography eluting with 1% MeOH/DCM to afford Int-5 (0.6 g, 20%). Mass (m/z): 244 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 8.51 (t, J=5 Hz, 2H), 7.71 (s, 1H), 7.63-7.55 (m, 2H), 7.34 (t, J=7 Hz, 1H), 6.94 (t, J=7 Hz, 1H), 2.43 (s, 3H). To a stirred solution of Int-5 (1.0 g, 4.1 mmol) and methyl 4-aminobenzoate (0.24 g, 4.9 mmol) in 1,4-dioxane (15 mL) were added Pd(OAc)2 (0.037 g, 0.163 mmol), xanthpos (0.142 g, 0.245 mmol) followed by Cs2CO3 (2.0 g, 6.1 mmol) were added to the reaction mixture under N2 atmosphere. The resulting reaction mixture was heated at 100 C. for 16 hours. After reaction completion, the volatiles were concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get crude product. The obtained crude material was purified by column chromatography eluting with 1% MeOH/DCM to afford Int-6 (0.788 g, 54%). Mass (m/z): 359 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 8.4 (d, J=7.6 Hz, 1H), 8.2 (d, J=7.6 Hz, 1H), 8.0 (d, J=8.4 Hz, 2H), 7.6 (d, J=7.6 Hz, 1H), 7.5 (d, J=8.4 Hz, 2H), 7.2 (s, 1H), 6.96 (s, 2H), 6.85 (m, 2H), 3.8 (s, 3H), 2.7 (s, 3H). A mixture of Int-6 (0.8 g, 2.23 mmol) in 4 N HCl (16 mL) was stirred at 100 C. for 3 hours. The reaction mixture was allowed to room temperature and continued stirring for another 30 minutes. The precipitate solid was filtered off and dried under vacuum to afford Int-7 (0.613 g, 80%) as a solid. Mass (m/z): 345 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 8.4 (d, J=7.6 Hz, 1H), 8.2 (d, J=7.6 Hz, 1H), 8.0 (d, J=8.4 Hz, 2H), 7.6 (d, J=7.6 Hz, 1H), 7.5 (d, J=8.4 Hz, 2H), 7.2 (s, 1H), 6.96 (s, 2H), 6.85 (m, 2H), 2.7 (s, 3H). To a stirred solution Int-7 (0.5 g, 1.45 mmol) in DMF (10 mL) were added HOBt (0.195 g, 1.44 mmol), EDCI.HCl (0.605 g, 3.16 mmol) and DIPEA (0.65 mL) at 0 C. After 5 minutes, NH2OTHP (0.37 g, 3.18 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 16 hours. After the completion, the reaction mixture was diluted with water (20 mL) and stirred for 30 minutes. The precipitated solid was filtered off, washed with water and dried under vacuum. The crude material was purified over silica gel column chromatography eluting with 3% MeOH/DCM to afford Int-8 (0.4 g, 62%). Mass (m/z): 444 [M++1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | To a stirred solution of Int-1 (3.0 g, 24 mmol) in EtOH (150 mL) was added Na2CO3 (3.8 g, 35 mmol) at room temperature and stirred for 15 minutes, then Int-2 (3.4 g, 36 mmol) was added and the reaction mixture was stirred at 80 C. for 16 hours. The volatiles were concentrated under reduced pressure and the residue was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (3×200 mL) and the combined organic extracts were washed with water (50 mL), brine (2×75 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to afford Int-3 (2.5 g) as crude oil. This crude compound was taken to the next stage without any further purification. 1H NMR (200 MHz, dmso-d6): delta 7.83 (d, J=12 Hz, 1H), 7.18 (brs, 1H), 6.8 (s, 1H), 6.45 (d, J=12 Hz, 1H), 3.85 (s, 3H), 2.4 (s, 3H). To a stirred solution of Int-3 (2.5 g, 15 mmol) in acetonitrile (60 mL) was added NIS (4.1 g, 18 mmol) portion wise at room temperature and stirred for 2 hours. After the reaction completion, the reaction mass was diluted with excess water and the stirring was continued for another 30 minutes. The precipitated solid was filtered off and dried under vacuum to afford Int-4 (3.5 g, 79%) as solid. Mass (m/z): 389 [M++1]. 1H NMR (200 MHz, CDCl3): delta 7.85 (d, J=12 Hz, 1H), 6.85 (brs, 1H), 6.6 (d, J=12 Hz, 1H), 3.9 (s, 3H), 2.45 (s, 3H). Int-4 (3.5 g, 12 mmol) was dissolved in DME-H2O (200 mL, 3:1) and purged with N2 for 15 minutes. Then PdCl2(dppf)-DCM (1.9 g, 2.4 mmol) and Int-5 (1.5 g, 9.6 mmol) were added and stirred for 10 minutes, finally Na2CO3 (1.9 g, 18 mmol) was added and the reaction mixture was stirred at 100 C. for 6 hours. After the completion of reaction, the volatiles were concentrated under vacuum. The residue was diluted with ice water (20 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude material, which was purified by column chromatography using 2% MeOH/DCM to afford Int-6 (0.7 g, 21%). Mass (m/z): 274.1 [M++1]. 1H NMR (200 MHz, CDCl3): delta 8.5 (d, J=6.8 Hz, 1H), 8.1 (d, J=6.8 Hz, 1H), 7.4 (s, 1H), 7.3 (m, 1H), 6.85 (m, 1H), 6.6 (d, J=12 Hz, 1H), 3.9 (s, 3H), 2.5 (s, 3H). To a stirred solution of Int-6 (0.7 g, 2.5 mmol) in acetonitrile (10 mL) were added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (0.07 g, 0.076 mmol), Xanthpos (0.106 g, 0.2 mmol), Cs2CO3 (1.49 g, 4.6 mmol) and Int-7 (0.38 g, 2.5 mmol) at room temperature under argon purging, then stirred for 1 hour. The reaction mixture was heated to 100 C. for 16 hours. After the reaction completion, the volatiles were concentrated under reduced pressure. The residue was washed with ether, diluted with water and stirred for 15 minutes. The precipitated solid was filtered and dried under vacuum to afford Int-8 (0.240 g, 24%). Mass (m/z): 390 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.2 (brs, 1H), 8.8 (brs, 1H), 8.35-8.45 (m, 2H), 8.25-8.18 (m, 1H), 7.82-7.95 (m, 1H), 7.15 (d, J=6.6 Hz, 1H), 7.0 (s, 1H), 7.0 (s, 1H), 6.65-6.76 (m, 1H), 3.85 (s, 3H), 2.45 (s, 3H). To a stirred solution of Int-8 (0.24 g, 0.61 mmol) in MeOH-DCM (25 mL, 3:1) was added 50% NH2OH (6 mL) at 0 C. After being stirred for 10 minutes at 0 C., a solution of NaOH (0.2 g) in water (2 mL) was added and stirred for additional 30 minutes at 0 C. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The volatiles were concentrated under reduced pressure after the reaction completion. The residue was diluted with water (15 mL) at 0 C., acidified to about pH 7 using 2 N HCl and stirred for 10 minutes. The precipitated solid was filtered and dried under vacuum to afford the title compound (0.15 g, 62%) as a solid. Mass (m/z): 391 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.2 (brs, 1H), 9.0 (brs, 1H), 8.6 (s, 1H), 8.35-8.45 (m, 2H), 7.85-8.05 (m, 2H), 7.78 (d, J=12.5 Hz, 1H), 7.08 (d, J=6.6 Hz, 1H), 7.0 (s, 1H), 6.65-6.75 (m, 1H), 6.41 (brs, 1H), 3.85 (s, 3H), 2.45 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 0.333333h;Sealed tube; Microwave irradiation; | INTERMEDIATE 216-(2-Chloropyridin-4-yl)quinoxalineA mixture of <strong>[50998-17-9]<strong>[50998-17-9]6-bromoquinoxalin</strong>e</strong> (1.07 g, 5.14 mmol), 2-chloropyridine-4- boronic acid (810 mg, 5.14 mmol), 2M aqueous sodium carbonate solution (5.5 mL, 11 mmol) and Pd(PPh3)4 (178 mg, 0.15 mmol) in DME (11 mL) was heated to 1200C in a sealed tube, under microwave irradiation, for 20 minutes. After cooling, the mixture was partitioned between water and EtOAc (100 mL each). The aqueous phase was extracted with EtOAc/THF (4: 1, 50 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was washed with diethyl ether/THF (9: 1, 30 mL) to give the title compound (790 mg, 64%) as a brown solid. deltaH (CDCl3) 8.89-8.97 (m, 2H), 8.54 (d, IH), 8.39 (d, IH), 8.26 (d, IH), 8.03 (dd, IH), 7.72 (s, IH), 7.60 (dd, IH). LCMS (ES+) 242 (M+H)+, RT 2.87 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; for 18h;Inert atmosphere; Reflux; | Step 5.4. tert-Butyl 4-[3-(2-chloropyrid-4-yl)-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate (According to Scheme 5b) To a suspension of 1.25 g (2.39 mmol) of tert-butyl 4-[2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate in a mixture of tetrahydrofuran and water are added 2.33 g (7.17 mmol) of cesium carbonate and 0.45 g (2.9 mmol) of <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong>. After sparging with a stream of argon for a few moments, 0.18 g (0.21 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloro)palladium(II) (PdCl2(dppf)) is added and the reaction mixture is refluxed under argon for 18 hours. The solvent is then stripped off under reduced pressure, the residue is taken up in chloroform, the organic phase obtained is washed with water, dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The brown solid obtained is purified by chromatography on silica gel (50 g), eluding with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5). The product obtained is crystallized from 20 ml of refluxing acetonitrile to give 0.95 g of a white powder after cooling, filtering off and drying. Yield: 78% 1H NMR (CDCl3) delta: 8.25 (d, 1H), 7.70 (d, 1H), 7.60 (s, 1H), 7.45 (pseudo q, 2H), 7.25 (d, 1H), 6.95 (pseudo t, 2H), 6.80 (d, 1H), 3.25-3.50 (m, 8H), 1.35 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis(triphenylphosphine)palladium(II)-chloride; In 1,2-dimethoxyethane; water; at 120℃; for 0.166667h;Microwave irradiation; | To a mixture of 3-(3-Bromo-imidazo-[1,2-b]-pyridazin-7-yl)-N-methyl-benzamide (Intermediate A) (1 eq, 0.353 mmol, 117 mg) and <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (1.2 eq, 0.424 mmol, 66.7 mg) in DME (3 ml) are added water (1 ml) and Na2CO3 (2 eq, 0.707 mmol, 87.6 mg). PdCl2(PPh3)2 (0.1 eq, 0.035 mmol, 24.8 mg) is then added and the reaction mixture is heated using microwave radiation at 120 C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-N-methyl-benzamide as a yellow solid; [M+H]+=364 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; lithium hydroxide;bis(triphenylphosphine)palladium(II)-chloride; In 1,2-dimethoxyethane; at 120℃; for 0.833333h;Microwave irradiation; | [3-Bromo-7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester (1 eq, 0.159 mmol, 65 mg) and <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (1.2 eq, 0.191 mmol, 30.1 mg) are dissolved in DME (3 ml) and water (0.75 ml) and Na2CO3 (3 eq, 0.478 mmol, 50.6 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.59 mg) is then added and the reaction mixture is heated using microwave radiation at 120 C. for 50 min. At the completion of this time the solvent is evaporated and the reaction mixture is dissolved in MeOH, filtered and the solvent is removed in vacuo to yield 3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo-[1,2-b]-pyridazin-7-yl]-N-methyl benzamide as a yellow solid; [M+H]+=379 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 110℃; for 16h;Sealed tube; | To a sealed tube was added N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2-(4- iodophenyl)acetamide 177-2 (100 mg, 0.22 mmol), 2-chloropyridin-4-ylboronic acid 177-3 (52 mg, 0.33 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), saturated Na2CO3 (1 mL), ethanol (1 mL) and toluene (3 mL). The reaction was heated to 110C and stirred for 16 hours. The reaction was cooled down to room temperature, then extracted with ethyl acetate. The crude product was purified by silica-gel flash chromatography, eluted with ethyl acetate to give N-(5-(4- acetylpiperazin-l-yl)pyridin-2-yl)-2-(4-(2-fluoropyridin-4-yl)phenyl)acetamide 177 as off-white solid. MS m/z 450.1 (M + 1); 1H NMR 400 MHz (DMSO-d6) deltaltheta.51 (s, IH), 8.40 (d, IH), 7.97 (d, IH), 7.87 (d, IH), 7.78 (d, IH), 7.76 (d, 2H), 7.69 (dd, IH), 7.43 (d, 2H), 7.37 (dd, IH), 3.68 (s, 2H), 3.52 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | 4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazole (0.73 g) and <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (0.20 g) were dissolved in dry DMF (2 mL) under inert atmosphere and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II)(102 mg) was added followed by caesium carbonate (0.84 g). The mixture was heated to 80 C. and stirred for 2 h. After cooling to room temperature the reaction mixture was diluted with DCM and the inorganic salts filtered off. The filtrate was washed with water and brine, dried under Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (20 g Isolute silica gel cartridge; gradient elution: hexane/EtOAc from 10/0 to 8.5/1.5) affording the title compound (144 mg). HPLC (Rt)=1.39 min (method M) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere; | To a mixture of 2-bromo-thiophene (1 g, 6.1 mmol) and <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (1.6 g, 10.2 mmol) in 50 ml_ of anhydrous DMF was added 2M Na2C03 (10 ml). After degassing the mixture for 15 min, Pd(PPh3)4 (5 moi %) was added and the mixture was heated at 100X for 24 h and cooled to room temperature. The solvent was removed under reduced pressure and the residue was taken in ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous MgS04. The crude compound, after the evaporation of the solvent, was purified by silica gel column chromatography (50% DCM in hexane) to give 2-chloro-4-thiophen-2-yl-pyridine (936 mg). 1H NMR (300 MHz, DMSO-cf6) 5: 8.63 (d, 1H) 7.27 (d, 1 H) 7.20 (dd, 1 H) 7.15 (d, 1 H) 7.09-7.05 (m, 2H) ; MS (ES) mlz (M+H) 196.7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere; | Exam le 2 - Synthesis of 5-bromo-2'-chloro-[3,4']bipyridinylA solution of 9.63 g (33.9 mmol) <strong>[233770-01-9]3-bromo-5-iodopyridine</strong>, 4.85 g (30.8 mmol) 2- chloro-pyridine-4-boronic acid and 3.11 g (37.0 mmol) sodium bicarbonate in 120 ml DMF and 30 ml water is heated to 80 C under nitrogen. 433 mg (0.616 mmol) bis- (triphenylphosphine)-palladium(ll)-chloride are added and the mixture is stirred for 4 hrs at 80 C. Water is added to the reaction mixture and the resulting precipitate is filtered off and washed well with water. The residue is dried under vacuum and recrystallized from 2-propanol yielding 5-bromo-2'-chloro-[3,4']bipyridinyl as brown crystals; HPLC-MS: 2.16 min, [M+H] 271.H NMR (400 MHz, DMSO) delta = 9.06 (d, J=2.0, 1 H), 8.83 (d, J=2.1 , 1 H), 8.60 (t, J=2A , 1 H), 8.53 (d, J=5.2, 1 H), 8.04 (d, J=1.6, 1H), 7.89 (dd, J=5.2, 1.6, 1 H). | |
With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere; | Example 2 Synthesis of 5-bromo-2'-chloro-[3,4']bipyridinyl A solution of 9.63 g (33.9 mmol) <strong>[233770-01-9]3-bromo-5-iodopyridine</strong>, 4.85 g (30.8 mmol) 2-chloro-pyridine-4-boronic acid and 3.11 g (37.0 mmol) sodium bicarbonate in 120 ml DMF and 30 ml water is heated to 80 C. under nitrogen. 433 mg (0.616 mmol) bis-(triphenylphosphine)-palladium(II)-chloride are added and the mixture is stirred for 4 hrs at 80 C. Water is added to the reaction mixture and the resulting precipitate is filtered off and washed well with water. The residue is dried under vacuum and recrystallized from 2-propanol yielding 5-bromo-2'-chloro-[3,4']bipyridinyl as brown crystals; HPLC-MS: 2.16 min, [M+H] 271. 1H NMR (400 MHz, DMSO) delta=9.06 (d, J=2.0, 1H), 8.83 (d, J=2.1, 1H), 8.60 (t, J=2.1, 1H), 8.53 (d, J=5.2, 1H), 8.04 (d, J=1.6, 1H), 7.89 (dd, J=5.2, 1.6, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;palladium diacetate; tris-(o-tolyl)phosphine; In 1,2-dimethoxyethane; water; at 80℃; for 5h;Inert atmosphere; | To a resealable reaction vessel under nitrogen was added 1.0 equiv of 48, Pd(OAc)2 (0.1 equiv), P(o-tolyi)3 (0.2 equiv), sodium carbonate (2.0 equiv) and the respective pyridinyl boronic acid (1.6 equiv), DME (6 mL) and water (0.7 mL). The mixture was degassed through bubbling nitrogen for 40 min and heated at 80 C for 5 h. The mixture was cooled, poured into 20 mL of a saturated aqueous solution of NaHC03 (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over MgS04, filtered through Celite and the solvent removed under reduced pressure. The resultant residue was purified by flash chromatography (EtOAc/ hexanes).7-teri-Biitoxycarbonyl-2-i? i?-[3'-(2-chloropyridin-4-yl)-5'-pyridnyl]-7- azabicyclo [2.2.1] heptane (49).The reagents were compound 48 and <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong>. NMR (300 MHz, CDCI3) delta 1.45 (br s, 9H), 1.48-1.69 (m, 2H), 1.87-1.91 (m, 3H), 2.05-2.12 (m, 1H), 2.98-3.03 (m, 1H), 4.29 (s, 1H), 4.43 (br s, 1H), 4.54 (s, 2 NH), 7.46 (dd, J = 1.5, 4.2 Hz, 1H), 7.55 (s, 1H), 7.94 (t, J = 2.0 Hz, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H); 13C NMR (CDC13) delta 28.3 (3 C), 28.8, 29.7, 40.5, 45.3, 55.9, 61.7, 79.9, 120.3, 122.0, 132.4, 132.5, 141.7, 145.8, 148.5, 150.0, 150.2, 152.4, 154.9; MS (ESI) m/z 386.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Intermediate 473-(2-Chloropyridin-4-yl)-4-(tetrahydro-2H-py n-4-yloxy)^^To a microwave vial was charged 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl- H- pyrazolo[4,3-c]pyridine (1.00 g, 1.70 mmol) , 2-chloropyridin-4-ylboronic acid (0.281 g, 1.79 mmol) and bis(diphenylphosphino)ferrocenepalladium chloride (139 mg, 0.170 mmol).Acetonitrile (11 mL, 210 mmol) and 1.0 M of potassium acetate in water (4.1 mL) were then added and the reaction mixture was degassed with nitrogen for 10 minutes and then heated to 100 C under microwave irradiation for 30 minutes. Upon reaction completion, the reaction mixture was diluted with dichloromethane, filtered through Celite and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 0-100% EtOAc in heptane to give the title compound (0.648 g, 66%). LC-MS (Method H): m/z = 573.4 [M+H]+; 1.56 min. H-NMR (400 MHz, CDCI3): delta 8.37 (d, J = 5.2, 1 H), 8.13 (s, 1 H), 7.80 (d, J = 5.2,1 H), 7.54 (d, J = 6.2, 1H), 7.35 - 7.27 (m, 9H), 7.22 - 7.14 (m, 6H), 5.90 (d, J = 6.2, 1 H), 5.55 - 5.46 (m, 1H), 4.01 - 3.92 (m, 2H), 3.69 - 3.60 (m, 2H), 2.23 - 2.13 (m, 2H), 1.99 - 1.87 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 100℃; for 0.666667h;Inert atmosphere; Microwave irradiation; | Intermediate 483-(2-Chloropyridin-4-yl)-4-methoxy-1-trityl- 1 H-pyrazolo[4, 3-c]pyridine TrTo a microwave vial was charged 3-iodo-4-methoxy-1-trityl-1 Y-pyrazolo[4,3-c]pyridine (1.14 g, 2.21 mmol) , 2-chloropyridin-4-yIboronic acid (0.366 g, 2.32 mmol) andbis(diphenylphosphino)ferrocenepalladium chloride (181 mg, 0.221 mmol). Acetonitrile (14 ml_, 270 mmol) and 1.0 M of potassium acetate in water (5.3 ml_) were then added and the reaction mixture was degassed with nitrogen for 10 minutes and then heated to 100 C under microwave irradiation for 40 minutes. Upon reaction completion, the reaction mixture was diluted with dichloromethane, filtered through Celite and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 0-2% EtOAc in DCM to give the title compound (0.887 g, 80%). LC-MS (Method H): m/z = 503.3 [M+Hf, 1.55 min. 1H-NMR (400 MHz, CDCI3): delta 8.38 (d, J = 4.6, 1 H), 8.06 (s, 1 H), 7.86 (d, J = 4.8, 1 H), 7.58 (d, J = 6.0, 1H), 7.35 - 7.28 (m, 9H), 7.23 - 7.14 (m, 6H), 5.91 (d, J = 6.2, 1H), 4.11 (s, 3H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 160℃; for 0.333333h;Microwave irradiation; | A mixture of 4-chlorophthalazin-1(2H)-one (300 mg, 1.66 mmol), 2-chloropyridin-4-ylboronic acid (314 mg, 1.99 mmol), Cs2CO3 (1080 mg, 3.32 mmol) and PdCl2(dppf) (71.5 mg, 0.083 mmol) in dioxane (6 mL) was heated at 160 C. under microwave condition for 20 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (APCI) M/Z 257 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.61% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.0833333h;Inert atmosphere; Microwave irradiation; | Example 68: 5-(2-Chloro-4-pyridinyl)-3-(1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-indole-7- carboxamide.To a mixture of (2-chloro-4-pyridinyl)boronic acid (0.095 g, 0.606 mmol), 5-bromo-3-(1 ,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-indole-7-carboxamide (0.075 g, 0.202 mmol) and potassium carbonate (0.168 g, 1.212 mmol) was added 1 ,4-dioxane (0.898 mL)/water (0.449 mL). The mixture was degassed with nitrogen and PdCI2(dppf) (0.015 g, 0.020 mmol) was added. The reaction mixture was heated in a microwave oven at 100 0C for 5 minutes on 'high' absorption setting. LCMS of crude reaction mixture shows the desired m/z and some unreacted starting material (very close ret. times). The reaction mixture was filtered through a Thiol SPE cartridge (500 mg) eluting with 1 :1 MeOH/DCM (10 mL). The filtrate was purified with RP-HPLC (XBridge Column, 0.1 % NH4OH). The fractions containing the desired compound are combined and concentrated to give 5-(2-chloro-4- pyridinyl)-3-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-indole-7-carboxamide (0.016 g, 19.61 %). LCMS : m/z 404.0 (M+H) Rt 0.89 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 1h;microwave irradiation; | R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-l-yl)-2'-vinyl-3,4'- bipyridine-5-carbonitrile (Compound 390)A mixture of 7-1 (410 mg, 1.01 mmol), 2-chloropyridin-4-ylboronic acid (237 mg, 0.95 mmol), K2C03 (414 mg, 3.03 mmol) and Pd(PPh3)4 (40 mg, 0.035 mmol) in DMF (2mL) was stirred at 150C in the microwave reactor for lh. The resultant mixture was partitioned between EtOAc and water, the organic phase was washed with water, brine and concentrated and purified by prepTLC (PE:EA=1 :1) to give 375 mg of (R)-2'-chloro-2-cyclopropyl-6-(4-(3- methoxypropanoyl)-3-methylpiperazin- 1 -yl)-3,4'-bipyridine-5-carbonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18 mg | With copper diacetate; triethylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere; | A mixture of the compound prepared in step 1 18.1 (100 mg, 0.252 mmol), 2-chloro-pyridine- 4-boronic acid (48 mg, 0.303 mmol), triethylamine (76 mg), and copper(ll) acetate (23 mg, 0.5 mmol) in CH2CI2(5 ml.) was stirred for 16 h at rt, under a nitrogen atmosphere. The reaction mixture was quenched by addition of water and extracted with EtOAc. The organic layer was dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, 3:1 ) to provide 18 mg of the title compound. tR: 6.26 min (HPLC 2); ESI-MS: 507.1 [M+H]+(LC-MS 2); Rf= 0.46 (hexane/EtOAc, 1 : 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | General procedure: In a muwave vial, 4-(4-(3-iodopyrazolo[1,5-a]pyrimidin-6-yl)phenyl)morpholine, 12, (17 mg, 0.041 mmol, 1.0 eq), phenyl boronic ester (6.0 mg, 0.046 mmol, 1.1eq), and Pd(dppf)Cl2?DCM (2 mg, 0.002 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuo and purged with Argon (3x). To the mixture was added 1,4-dioxane (2 mL), followed by a solution of K3PO4 (18 mg, 0.084 mmol, 2.0 eq) in H2O (1.0 mL). The reaction was heated to 120 C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1:1, 40 mL). The organic layer was separated, washed with H2O (15 mL), Brine (15 mL), dried (MgSO4), filtered and concentrated. The material was purified by reverse-phase HPLC (25-85% acetonitrile: H2O w/ 0.1% TFA) to afford 4-(4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl)morpholine, 13e, (8.3 mg, 43% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | General procedure: In a muwave vial, 4-(4-(3-iodopyrazolo[1,5-a]pyrimidin-6-yl)phenyl)morpholine, 12, (17 mg, 0.041 mmol, 1.0 eq), phenyl boronic ester (6.0 mg, 0.046 mmol, 1.1eq), and Pd(dppf)Cl2?DCM (2 mg, 0.002 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuo and purged with Argon (3x). To the mixture was added 1,4-dioxane (2 mL), followed by a solution of K3PO4 (18 mg, 0.084 mmol, 2.0 eq) in H2O (1.0 mL). The reaction was heated to 120 C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1:1, 40 mL). The organic layer was separated, washed with H2O (15 mL), Brine (15 mL), dried (MgSO4), filtered and concentrated. The material was purified by reverse-phase HPLC (25-85% acetonitrile: H2O w/ 0.1% TFA) to afford 4-(4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl)morpholine, 13e, (8.3 mg, 43% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | General procedure: In a muwave vial, 4-(4-(3-iodopyrazolo[1,5-a]pyrimidin-6-yl)phenyl)morpholine, 12, (17 mg, 0.041 mmol, 1.0 eq), phenyl boronic ester (6.0 mg, 0.046 mmol, 1.1eq), and Pd(dppf)Cl2?DCM (2 mg, 0.002 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuo and purged with Argon (3x). To the mixture was added 1,4-dioxane (2 mL), followed by a solution of K3PO4 (18 mg, 0.084 mmol, 2.0 eq) in H2O (1.0 mL). The reaction was heated to 120 C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1:1, 40 mL). The organic layer was separated, washed with H2O (15 mL), Brine (15 mL), dried (MgSO4), filtered and concentrated. The material was purified by reverse-phase HPLC (25-85% acetonitrile: H2O w/ 0.1% TFA) to afford 4-(4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl)morpholine, 13e, (8.3 mg, 43% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56%; 31% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | A mixture of intermediate 5a (500 mg; 1.024 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (242 mg; 1.537 mmol), K3P04 (435 mg; 2.05 mmol) and S-Phos (84 mg; 0.21 mmol) in 1 ,4- dioxane (12 ml_) and H20 (5 mL) was degassed with N2. After 10 min, Pd2(dba)3 (94 mg; 0.10 mmol) was added portionwise. The r.m. was heated at 80C for 3 h, cooled to r.t, poured onto ice water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (Irregular SiOH 15-40pm 300g; mobile phase: 60% heptane, 40% EtOAc). The pure fractions were collected and evaporated to dryness yielding 325 mg (56%) of intermediate 62 and 207 mg (31 % of intermediate 63. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 4.5h;Microwave irradiation; Sealed tube; Inert atmosphere; | Preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate: (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (400.0 mg, 0.742 mmol), 2-chloro-4-pyridinylboronic acid (140.2 mg, 0.891 mmol), potassium carbonate (307.7 mg, 2.227 mmol), and Pd(PPh3)4 (128.7 mg, 0.111 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (3.5 mL) and water (0.7 mL). The reaction mixture was heated at 90 C. for 4.5 h then cooled to rt. The aqueous layer was separated and extracted three times with ethyl acetate. All organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the final compound. LCMS-ESI+: calc'd for C30H33Cl2N2O3S: 571.2 (M+H+). Found: 571.1 (M+H+); 1H NMR (400 MHz, CDCl3) delta 8.49 (d, J=4.9 Hz, 1H), 7.93 (s, 2H), 7.77 (d, J=5.0 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 4.82 (dd, J=8.9, 2.7 Hz, 1H), 4.42 (dd, J=11.2, 9.3 Hz, 1H), 4.29 (dd, J=11.5, 3.2 Hz, 1H), 2.80 (s, 3H), 1.14 (s, 9H), 0.97 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 95℃; for 2h; | Preparation of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: The reaction mixture of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (370 mg, 0.769 mol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (157 mg, 0.99 mmol), 2N K2CO3 (1.9 mL), Pd(PPh3)4 (80 mg, 0.077 mmol) in dioxane (10 mL) was heated at 95 C. for 2 h. The reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C26H24Cl2N2O3S: 515.1 (M+H+). Found: 515.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 120℃; for 2h;Sealed tube; | The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3- (trifluoromethylsulfonyloxy)phenyl)benzo[d]thiazol-6-yl)ethyl pivalate (30 mg, 0.0438 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (10 mg, 0.0657 mmol), 2N K2CO3 (100 muL), Pd(PPh3)4 (5.0 mg, 0.0044 mmol) in dioxane (2 mL) was heated at 120 C. in sealed tube for 2hs. The reaction was washed by sat. NaHCO3, extracted by EtOAc, dried by MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C36H36Cl2N2O3S: 647.2 (M+H+). Found: 647.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 90℃; for 6h;Inert atmosphere; | To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (858 mg, 1.73 mmol) and <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (327 mg, 2.08 mmol) in dioxane (14.6 mL) was added Pd(PPh3)4 (160 mg, 0.139 mmol) and 2N K2CO3 (3.6 mL, 7.28 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 90 C. for 6 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H27Cl2N2O3S: 529.1. Found: 529.2. Preparation of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 12h;Inert atmosphere; Reflux; | Example 46 Synthesis of 2-{6-[5-(2-chloro-pyridin-4-yl)-thiazol-2-ylamino]-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl}-ethanol [0332] 4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester 36 (0.43 g, 1 mmol), 2-chloropyridine - 4-boronic acid (0.23 g, 1.5 mmol) and sodium carbonate (0.3 g, 2 mmol) in mixture of dioxane/ water (6/2ml) tetrakis(triphenylphosphine)palladium (0) (0.006 g, 5%mol) was added under argon atmosphere. The mixture was refluxed for 12h (TLC control), then cooled to room temperature and dichloromethane (30 ml) and water (20 ml) were added. The product was extracted with dichloromethane (2x20 ml). The organic layers were dried over sodium sulfate. And concentrated in vacuo. The residue was purified by column chromatography on silica gel to provide the title product (0.35 g, 74%). [5-(2-Chloro-pyridin-4-yl)-thiazol-2-yl]-(1', 2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-yl)-amine dihydrochloride (45) [0334] Compound 45 was prepared according to the procedure as described for intermediate 23a (step d) from 6-[5-(2-chloro-pyridin-4-yl)-thiazol-2-ylamino]-3', 4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (0.35 g, 0.7 mmol). Yield 0.3 g (97%). 2-{6-[5-(2-chloro-pyridin-4-yl)-thiazol-2-ylamino]-3', 4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl}-ethanol [0335] A mixture of [5-(2-chloro-pyridin-4-yl)-thiazol-2-yl]-(1', 2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-yl)-amine dihydrochloride (0.15 g, 0.33 mmol), sodium bicarbonate (0.13 g, 1.5 mmol), 2-bromo-ethanol (0.25 g, 2 mmol) and anhydrous DMF (5 ml) was stirred at 70C for 24 h. (TLC, LCMS control). The reaction mixture was diluted with water (10 ml), formed precipitated was filtered off and dried. The product was purified by column chromatography on silica gel to afford the title compound (0.08 g, 58%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate; In 1,4-dioxane; at 85℃; for 4.5h;Schlenk technique; Inert atmosphere; | 2-Bromo-1-methyl-4-oxo-1 ,4,6,7 -tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (1.03 g, 3.13mmol), 2-chloro-4-pyridineboronic acid (0.98 g, 6.26 mmol) and PdCb(dppf)2 (0.26 g, 0.31 mmol) were charged in a15 Schlenk tube under argon. Degassed dioxane (52 ml) and a 2 M solution of Na2C03 (4.69 ml) were added and theresulting mixture was degassed three times back filling with argon each time. The reaction was heated at 85 oc for4.5 h. After cooling, it was filtered over a pad of celite rinsing thoroughly with EtOAc. The filtrate was washed with asaturated solution of NaHC03, water and brine. The organic layer was dried over anhydrous Na2S04, filtered andevaporated. Purification by flash column chromatography (Hex/EtOAc 50/50) afforded the title product as white solid20 (0.64 g, 56%).1H NMR (600 MHz, DMSO-da) o ppm 1.47 (s, 9 H) 2.97 (t, J=6.32 Hz, 2 H) 3.65 (s, 3 H) 3.98 (t, J=6.32 Hz, 2 H) 6.88(s, 1 H) 7.55 (dd, J=5.31, 1.47 Hz, 1 H) 7.62-7.64 (m, 1 H) 8.41 (d, J=5.31 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In tetrahydrofuran; water; for 2h;Reflux; | To a solution of 7-bromo-5-methyl-2-((4-(methylsulphonyl)piperazin-1-yl)methyl)thieno[3,2-c]pyridin- 4(5H)-one (for a preparation see Intermediate 69, 371 mg, 0.883 mmol) and (2-chloropyridin-4- yl)boronic acid (208 mg, 1 .324 mmol) in tetrahydrofuran (30 ml.) were successively added sodium carbonate (2M in water) (1.545 ml_, 3.09 mmol) and 1 ,1 '-5/s(diphenylphosphino)ferrocene- palladium(ll) dichloride-dichloromethane complex (72.1 mg, 0.088 mmol). The reaction mixture was refluxed for 2 hours, whereupon it was allowed to cool to room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with 2 - 10% methanol in dichloromethane. The appropriate fractions were combined and concentrated in vacuo to give 7-(2- chloropyridin-4-yl)-5-methyl-2-((4-(methylsulphonyl)piperazin-1-yl)methyl)thieno[3,2-c]pyridin-4(5H)- one (265 mg, 0.585 mmol, 66%) as a dark brown solid. LCMS (2 min, Formic Acid): Rt = 0.77 min, MH+ = 453/455 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In tetrahydrofuran; water; for 2h;Reflux; | To a solution of 2-((1 ,4-oxazepan-4-yl)methyl)-7-bromo-5-methylthieno[3,2-c]pyridin-4(5H)-one (for a preparation see Intermediate 42, 220 mg, 0.616 mmol) and <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (145 mg, 0.924 mmol) in THF (20 mL) were successively added sodium carbonate (2M in water) (0.924 mL, 1.847 mmol) and PdCI2(dppf)-DCM adduct (50.3 mg, 0.062 mmol). The reaction mixture was refluxed for 2 hours, whereupon it was allowed to cool to rt. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and water. The aqueous phase was extracted three times with EtOAc and the combined organic layers were washed with brine, dried over MgSC , filtered and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel eluting with 2 to 10% MeOH in DCM. The appropriate fractions were combined and concentrated in vacuo to give 2-((1 ,4-oxazepan-4-yl)methyl)-7-(2-chloropyridin-4-yl)- 5-methylthieno[3,2-c]pyridin-4(5H)-one (158 mg, 66%) as a light yellow solid. LCMS (2 min, Formic Acid): Rt = 0.54 min, MH+ = 390 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; | 7-(2-chloropyridin-4-yl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (4). A mixture of 7-bromo-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (21 mg, 0.1 mmol), 2- chloro-4-pyrridoboronic acid (25 mg, 0.15 mmol), PdCl2(dppf) (8 mg, 0.01 mmol) and cesium carbonate (65 mg, 0.2 mmol) in a 40 mL vial was vacuumed and refilled with nitrogen, followed by addition of dioxane/water (5/1 mL). The final mixture was stirred at 100 C for 4 h. The reaction was cooled to room temperature. Water was added, and the reaction was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column purification (10% methanol in dichloromethane) to provide the product a light yellow powder (10 mg, 40%). MS m/z (M+H): 248.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 10h;Inert atmosphere; | General procedure: Toa suspension of compound 4 (0.15 g,0.32 mmol) in 1,2-DME and water (1:1, 8 mL), sodium carbonate (0.104 g, 0.98mmol) was added. The reaction mixture was degasified for 15 min. To the degasified reaction mixture was added boronic acid (0.39 mmol) and PdCl2(PPh3)2 (0.002 g, 0.03 mmol) under nitrogen atmosphere. The reaction mixture was then heated at 100 C for 10 h (monitored by TLC) and cooled to room temperature and then diluted with water and extracted with ethyl acetate (3x20ml). Combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and filtered. Solution was evaporated and the residue was purified by silica gel column chromatography using chloroform-methanol (95:5)mixture as eluent and further solidified by dissolving with minimum volume of dichloromethane followed by addition of hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 150℃; for 0.166667h;Microwave irradiation; | Intermediate 26 and final compound 215 (1-26 and Co. No. 215) 3-(2-Chloro-pyridin-4-yl)-75'-methyl-5-(4-trifluoromethyl-phenyl)-6,7-dihydro-5H- pyrazolo[l,5-a]pyrazin-4-one (1-26 and Co. No. 215) This reaction was divided in four batches to a combined total amount indicated herein and combined for workup and purification. Pd(PPh3)4 (401 mg, 0.35 mmol) was added to a stirred suspension of intermediate 1-23 (2.92 g, 6.94 mmol) and 2-chloropyridine- 4-boronic acid (1.42 g, 9.02 mmol) in 1,4-dioxane (39 mL) and a sat. sol. of NaHC03 (19.5 mL). The mixture was stirred at 150 C for 10 min under microwave irradiation. Then the mixture was diluted with H20 and extracted with DCM. The organic layer was separated, dried (Na2S04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield intermediate compound 1-26 as a yellow solid (1.84 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 110℃; for 1h;Microwave irradiation; | 2,6-Dichloro-4-(2-chloro-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prepared from the sulphonamide of intermediate 2 (250 mg, 0.6 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (108 g, 0.67 mmol), tribasic potassium phosphate (145 mg, 0.68 mmol), Pd(dppf)Cl2.DCM (20 mg, 0.024 mmol) and water (0.3 ml) in oxygen-free DMF (2.5 ml) at 110 C. for 1 h according to the method of intermediate 11, to give the title compound as a white solid (212 mg, 0.47 mmol, 79%). deltaH (CDCl3, 300K) 8.38 (1H, dd J 0.5 Hz 5.2 Hz), 7.54 (2H, s), 7.37 (1H, dd J 1.6 Hz 5.2 Hz), 6.56 (1H, s), 3.65 (3H, s), 2.09 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 447.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 130℃; for 1h;Microwave irradiation; | Prototypical Procedure for Suzuki Coupling of a Boronic Ester or Boronic Acid with an Aryl Halide; METHOD 1: A solution of the compound of intermediate 1 (1.5 g, 4.36 mmol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (684 mg, 4.35 mmol), tribasic potassium phosphate (924 mg, 4.35 mmol) and Pd(dppf)Cl2.DCM (100 mg, 0.12 mmol) and water (1.5 ml) in oxygen-free DMF (8 ml) was heated in a microwave at 130 C. for 1 h. The reaction was concentrated to dryness in vacuo, diluted with DCM (100 ml), washed with saturated aqueous sodium hydrogencarbonate solution (2*25 ml), dried (MgSO4) and concentrated in vacuo to give a residual oil. Chromatography (SiO2, EtOAc) gave the title compound as a fine white solid (1.13 g, 2.66 mmol, 61%). deltaH (D-6 DMSO, 300K) 8.52 (1H, d J 5.2 Hz 7.88 (2H, d J 8.4 Hz), 7.74 (2H, d J 8.4 Hz), 7.58 (1H, s), 7.46 (1H, dd J 1.5 Hz 5.2 Hz), 6.36 (1H, s), 3.71 (3H, s), 2.12 (3H, s), 1.62 (3H, s). m/z (ES+, 70V) 377.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | Step 1A stirred solution of the product from Step 7 of Scheme Q (5 g, 9.17 mmol), (2- chloropyridin-4-yl)boronic acid (1.875 g, 11.92 mmol) and potassium phosphate tribasic (5.84 g, 27.5 mmol) in 1,4-dioxane (100 ml) and Water (10 ml) was purged with argon for 15 mm. Then 1,1 ?-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.749 g, 0.917 mmol) was added and the mixture was heated at 100 C for 16 h. The reaction was cooled to rt and concentrated under vacuum. To the residue were added water and DCM. The organic layer was separated and the aqueous layer was extracted with DCM (x3). The combined organic layers were dried, filtered and concentrated to leave a residue which was purified by silica gel column chromatography (elution with 5:1 hexane:EtOAc) to yield Intermediate Ji. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; water; potassium carbonate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; | [0 140j To a solution of tert-butyl 2-methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)benzylcarbamate (3.47 g, 10 mmol) and 2,4-dichloropyrimidine (1.79 g, 12 mmol) in 1,4- dioxane (28 mL) and H20 (7 mL), Pd(dppf)C12.DCM (815 mg, 1.0 mmol) and K2C03 (2.76 g,mmol) were added under N2. The mixture was stirred at 90 C for 2 h. After cooling to rt, the mixture was diluted with H20 (80 mL) and extracted with EA (80 mL x2). The organic layers were dried and concentrated. The residue was purified by column chromatography (silica,petroleum ether/EtOAc = 5:1 to 2:1) to give tert-butyl 4-(2-chloropyrimidin-4-yl)-2- methylbenzylcarbamate (2.67 g, yield 80%) as white solid.[0364j Synthesis of 2-(tert-butyl)-N-((2?-chloro-6-methyl-[2,4?-bipyridin] -5- yl)methyl)thiazole-5 -carboxamide was similar to that of tert-butyl 4-(2-chloropyrimidin-4-yl)-2- methylbenzylcarbamate. The mixture was purified by silica gel column (petroleum ether/EtOAc = 1: 1) to give 2-(tert-butyl)-N-((2?-chloro-6-methyl-[2,4?-bipyridin]-5-yl)methyl)thiazole-5- carboxamide (80 mg, yield: 52%) as a yellow solid. ESI-MS (M+H) : 400.9. ?H NMR (400 MHz, CDC13) (5: 8.43 (d, J= 4.8 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.78 (dd, J 5.2, 0.8 Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 7.59 (d, J= 7.6 Hz, 1H), 6.36 (t, J 5.6 Hz, 1H), 4.67 (d, J 5.6 Hz, 2H), 2.67 (s, 3H), 1.45 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With palladium diacetate; sodium carbonate; tris-(o-tolyl)phosphine; In 1,2-dimethoxyethane; water; at 80℃; for 5h;Inert atmosphere; | General procedure: To a resealable reaction vessel under nitrogen was added1.0 equiv of compound 7, Pd(OAc)2 (0.1 equiv), P(o-tolyl)3(0.2 equiv), sodium carbonate (2.0 equiv) and the respective pyridinylboronic acid (1.6 equiv), DME (6 mL) and water (0.7 mL).The mixture was degassed through bubbling nitrogen for 40 min,sealed and heated in an oil bath at 80 C for 5 h. The mixture wascooled, poured into 20 mL of a saturated aqueous solution ofNaHCO3 (20 mL) and extracted with EtOAc (3 30 mL). The combinedorganic layers were dried over MgSO4, filtered through Celite and the solvent removed under reduced pressure. The resultantresidue was purified on a silica gel ISCO column and elutedwith EtOAc/hexanes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 3h;Inert atmosphere; Reflux; | a) Preparation of Int. 293 The mixture of Int. 289 (6.5 g; 14.6 mmol), B-(2-chloro-4-pyridinyl)-boronic acid (2.4 g; 15.3 mmol), Pd(PPh3)4 (1.69g; 1.46 mmol) and sat. aq. Na2C03 (20 ml) in dioxane (60 ml) was refluxed for 3 h under N2 atmosphere. The resulting mixture was poured into water and the precipitate was filtered, washed with water and dried. The crude was purified by column chromatography (eluent: PE/EtOAc 3/1). The desired fractions were collected and the solvent was evaporated. Yield: 5.5 g of Int. 293 (79 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux; | c) Preparation of Int. 8 Int. 1 (34.4 g; 104 mmol) was dissolved in dioxane (1000 ml). 2-Chloropyridine-4- boronic acid (18 g; 114 mmol), Pd(PPh3)4 (6.12 g; 2.12 mmol) and Na2C03 (2 M aq, solution) (235 ml) were added under N2 gas atmosphere. The mixture was refluxed overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography over silica gel (eluent: PE / EtOAc 10/1). The desired fractions were collected and the solvent was evaporated yielding 19 g of Int. 8 (53.0 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 2-5 eq of boronic acid derivative were added 0.15 mmol 2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl trifluoromethanesulfonate (0.25 M in NMP,600 iL), 30 imol 1,1-BIS(DIPHENYLPHOSPHINO)FERROCENE]DICHLOROPALLADIUM(II) (0.04 M in NMP, 750 iL) and 0.45 mmol potassium carbonate (1 M in water, 450 iL) and the mixture was heated in a microwave oven at 110C for 5 hours. After cooling, 0.9 mmol HCI (2M in water, 450 iL) were added and the mixture was heated in a microwave oven for 10 hours at 50C. Aftercooling, the mixture was filtered, washed with NMP and subjected to preparative HPLC to yield the target product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.6% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In tetrahydrofuran; water; at 70℃; for 6h; | Step 1 : A round-bottom flask was charged with <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (1 equiv), potassium carbonate (3.5 equiv), bis(triphenylphosphine)palladiurn dtchloride (0.025 equiv), 2: 1 THF/water (0.45 M), and 2-bromo-3,3,3-trifluoroprop-l-ene (1.2 equiv). The flask was fitted with a reflux condenser and heated to 70 C for 6 h. After cooling to room temperature, the mixture as diluted with water and extracted with EtOAc (3x, decanted away from a gray solid). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (10-60% EtO Ac/Heptane) to give 2-chloro-4-(3,3,3-trifluoroprop-l -en-2-yl)pyridine (47.6 % yield) as a pale-orange oil. 1H NMR (600 MHz, CHLOROFORM-d) delta ppm 8.46 (d, . 5.23 Hz, 1 H) 7.44 (s, 1 H) 7.32 (d, J=5.14 Hz, 1 H) 6,20 (s, 1 H) 6,03 (d, .1=0.73 Hz, 1 H). LCMS (m/z) (M+H) - 207.9, Rt = 1.39 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tris-(dibenzylideneacetone)dipalladium(0); tripotassium phosphate "n" hydrate; tricyclohexylphosphine tetrafluoroborate; In 1,4-dioxane; water; at 120℃; for 1.5h;Microwave irradiation; | Charge three separate microwave vials each with 2-bromo-5-(2-rnethoxyethyl)- 6,6-dimethyl-thieno[2,3-c]pyrrol-4-one (1 g, 3.3 mrnol), <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong>(580 mg, 3.62 mrnol), tris(dibenzyiideneacetone)dipaliadiurn(0) (152 mg, 0.16 nimol), tricyclohexylphosphine tetrafluoroborate (363 mg, 0.99 nunol), potassium phosphate tribasic N-hydrate (3.56 g, 16.8 mniol), water (7.6 mL) and 1,4-dioxane (8 mL). Heat the vials in a microwave reactor at 120 C for 90 minutes. Cool the vials to room temperature and combine the contents of the vials. Dilute the resulting mixture withEtOAc (3() mL) and add anhydrous sodium sulfate. Stir the mixture for i 5 minutes and filter the mixture through CELITE. Wash the solids with EtOAc and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography by loading the residue onto a 25 g pre-column and eluting the pre-column onto an additional 120 g silica gel column with a gradient from 5-25% acetone in hexanes to givethe title compound 2.55 g (77%). MS (mIz): 337 (M÷1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; water; at 60 - 80℃; for 7h;Inert atmosphere; | Treat a solution of 2-bromo-5-[2-(cyciopropoxy)ethyi]-6,6-dimethyl-thieno[2,3- c]pyrroi-4-one (15.8 g, 48 mmol) and 2-chioropyridine-4-boronic acid (10.5 g, 67 mmol) in EtOH (2 L) with sodium carbonate (2 M in water, 50 mL, 100 mrnol). Sparge the mixture with nitrogen for 15 minutes. Add trans-dichloro-bis-triphenylphosphine palladium (II) (1,0 g, IA mmoi). Sparge the mixture with nitrogen for an additional 15 minutes. Heat the reaction mixture at 60 C for five hours. Add additional <strong>[458532-96-2]2-chloropyridine-4-boronic acid</strong> (2.2 g) and heat the reaction at 80 C for an additional two hours. Cool the mixture to room temperature and dilute with EtOAc (200 mL). Wash the organic solution with saturated NaCI. Concentrate the organic solution under reduced pressure. Purify the residue by silica gel chromatography (220 g) eluting with a gradient from 0-10% acetone in DCM to yield the title compound 12.9 g (74%). MS (mlz): 363(M±i). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.4% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 120℃; for 2h; | The mixture of 1 -(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1.307 g, 5.084 mmol), (2-chloropyridin-4-yl)boronic acid (2.00 g, 12.71 mmol), Pd(dppf)2 DCM (0.627 g, 0.763 mmol) and potassium carbonate (1.405 g, 10.17 mmol) in dioxane (15 mL) was heated to 120C for 2 hours in a 20 mL heavy walled sealed tube under microwave radiation. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried with Na2SO4 and purified by Biotage chromatography (eluting with 15% EtOAc/Hex). The appropriate fractions were concentrated to give the title compound (432.6 mg, 1.493 mmol, 29.4 %) as an oil. LCMS m/z = 290.0 [M+1] ?H NMR (400 MHz, CDC13): oe ppm 4.03 (s, 2H), 7.04 (d, J= 4.80 Hz, 1H), 7.08 (d, J= 8.81 Hz, 1H), 7.16 (s, 1H), 7.28 (d, J= 6.02 Hz, 2H), 8.35 (d, J= 5.22 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 130℃; for 4h; | Preparation of compound 11-3[299]After dissolving compound 11-1 (4 g, 25.4 mmol), compound 11-2 (10.2 g, 38.1 mmol), Pd(PPh3)4(1.5 g, 1.3 mmol), and K2CO3(7.0 g, 50.8 mmol) in a mixture solvent of toluene 130 mL, EtOH 35 mL, and H2O 35 mL in a flask, the mixture was refluxed at 130C for 4 hours. After the reaction is completed, the reactant was extracted with EA, and the remaining product was then separated with column chromatography to obtain compound 11-3 (4.0 g, yield: 45%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 2.5h;Inert atmosphere; Reflux; | In a RB flask was added a mixture of 2,5-dibromo-3-nitropyridine (8.78 g, 31.1 mmol) and <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (5 g, 31.8 mmol) in tetrahydrofuran (60 mL) and the solution was purged under a stream of nitrogen. Added 2 M aqueous potassium phosphate (39.7 mL, 79 mmol) and continued purging with nitrogen and then added PdCl2(dppf)-CH2Cl2Adduct (1.297 g, 1.59 mmol) and the mixture was then heated to reflux under nitrogen for 2.5 h. Let cool to room temperature and diluted with water and extracted into ethyl acetate. Washed with water and concentrated. The material was dissolved in DCM and chromatographed on an ISCO Companion 120 g silica gel column and eluted with EtOAc/Hexane gradient (20-50%) to give 5-bromo-2'-chloro-3-nitro-2,4'- bipyridine (5 g, 15.9 mmol, 50.0 % yield). LCMS: RT = 0.92 min; (ES): m/z (M+H)+ = 314.0, 316.0. (Waters Acquity SDS. Column: BEH C18 2.1x50mm 1.7u (1.6 min grad) 2- 98 % B. Flow Rate = 0.8 mL/min. Solvent A: H2O -0.1 %TFA. Solvent B: Acetonitrile - 0.1 %TFA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.8 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 16h;Inert atmosphere; | To a stirred solution of N-({5-bromo-2-[(3-{ [(tert-butyldimethylsilyl)oxy]methyl}pyridin2-yl) sulfanyl] -3-chlorophenyl } methyl)-2-methylpropane-2- sulfinamide(2. 5g, 4.3mmol) indioxan (20 mL) were added <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (818 mg, 5.2mmol), Na2CO3(1.4g,l3mmol), water (10 mL) and degassed for 10 mm in argon atmosphere. To this was addedPd(PPh3)4 (SOlmg,0.43mmol) and again degassed for 5 mm. The reaction mass was heated to120C for 16 h. Reaction mixture was cooled to 25C, filtered through celite pad and washedwith EtOAc. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica column chromatography (Si02 100-200 mesh; 50-90% EtOAC/Hexanes) to get N-({2- [(3- { [(tert-butyldimethylsilyl)oxy] methyl }pyridin-2-yl) sulfanyl] -3-chloro-5-(2-chloropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (2.8g) as off white solid. LC-MS: 609.8 [M+H] + |
2.8 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 16h;Inert atmosphere; | To a stirred solution of N-({5-bromo-2-[(3-[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl} methyl)-2-methylpropane-2-sulfinamide(2.5g, 4.3mmol) in dioxan (20 mL) were added <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (818 mg, 5.2mmol), Na2C03 (1.4g,13mmol), water (10 mL) and degassed for 10 min in argon atmosphere. To this was added Pd(PPh3)4 (501 mg,0.43mmol) and again degassed for 5 min. The reaction mass was heated to 120C for 16 h. Reaction mixture was cooled to 25C, filtered through celite pad and washed with EtOAc. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica column chromatography (Si02; 100-200 mesh; 50-90% EtOAC/Hexanes) to get N-({2- [(3-[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-chloropyridin-4- yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (2.8g) as off white solid. LC-MS: 609.8 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 130℃; for 5h; | 1) Preparation of compound 1[163]After dissolving <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (10.0 g, 63.5 mmol), 2-([1,1'-biphenyl]-4-yl)-4-chloro-6-phenyl-1,3,5-triazine (32.8 g, 95.3 mmol), Pd(PPh3)4(3.7 g, 3.2 mmol), and K2CO3(17.6 g, 127 mmol) in toluene (320 mL), EtOH (80 mL), and H2O (80 mL) of a flask, the mixture was under reflux at 130 for 5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and then the obtained organic layer was dried with MgSO4to remove the remaining moisture, and subjected to column chromatography to obtain compound1(13.2 g, yield: 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 90℃; for 1h; | A solution of the compound from Example 16 step a (940 mg, 2.0 mmol), 6-chloropyridin-3- ylboronic acid (320 mg, 2.03 mmol), K2C03 (420 mg, 3.04 mmol), Pd(PPh3)2C12 (150 mg, 0.2 mmol), DME (20 mL), H20 (lOmL) in EtOH (20 mL) was hated at 90C for 1 h. The mixture was diluted with water, extracted with EtOAc. The organic phase was dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give thedesired compound as a yellow solid (1.12 g, 76%). ESI MS m/z = 501.25 [M+Hf |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | Step 1: Synthesis of 2-(1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)ethoxy)-5-(2-chloropyridin-4-yl)thiazolo[5,4-b]pyridine To a solution of 2-(1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)ethoxy)-5-bromothiazolo[5,4-b]pyridine (0.040 g, 0.000089 mol) and <strong>[458532-96-2]2-chloropyridin-4-yl-4-boronic acid</strong> (0.023 g, 0.11 mmol) in Dioxane (4 mL), K2CO3 (0.032 g, 0.23 mmol) (dissolved in water 1 mL) was added and reaction mixture purged with nitrogen for 30 min. To it, Pd(dppf)Cl2 (0.0065 g, 0.09 mmol) was added and again purged with nitrogen for 15 min. Now reaction mixture was heated at 100 C. for 2 h. Reaction progress was monitored on TLC for its completion. On completion, reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give crude reaction mass. Purification of the compound was done by silica gel (100-200No.) column chromatography and desired product start eluting at 7-10% EtOAc/N-Hexane to obtained 2-(1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)ethoxy)-5-(2-chloropyridin-4-yl)thiazolo[5,4-b]pyridine as white pinkish solid material. MS: 485 [M++1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; water; caesium carbonate; In 1,4-dioxane; at 100℃; for 4h; | To a mixture of degassed 1 ,4-dioxane (30 mL) and water (7 mL) in a dry pressure tube was added [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloro- methane (0.0225 g, 0.027 mmol), followed by the title compound from Preparative Example C (0.3 g, 0.545 mmol), <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (0.103 g, 0.654 mmol), and cesium carbonate (0.355 g, 1.09 mmol). The reaction mixture was then heated at 100C for 4 hours. The solvents were removed under reduce pressure and the residue was dissolved with ethyl acetate (40 mL) and water (50 mL), The phases were separated and the aqueous phase was extracted again with ethyl acetate (50 mL). The combined organics were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified on HP-Sil SNAP cartridges using a Biotage Isolera One purification system by employing a dichloromethane/methanol gradient (100/0 -> 90/10) to afford the title compound (0.153 g, 26%). (0270) 1H-NMR (400 MHz, DMSO-d6) delta = 12.48 (s, 1 H), 9.45 (s, 1 H), 8.83 (d, 1H), 8.57 (dd, 2H), 8.31-8.22 (m, 1 H), 8.22-8.13 (m, 2H), 7.53 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 80℃; | Synthetic procedure for the preparation of formula (I-e): Compound Y (77.5 mg, 0.207 mmol, 1 eq.) was dissolved in dioxane (6 mL). To this solution, an appropriate boronic acid (0.228 mmol, 1.1 eq), Pd(PPh3)2C12 (14.5 mg, 0.022 mmol, 0.1 eq.), and Cs2CO3 (0.675 mmol, of 1M solution, 3 eq.) were added. The reaction mixture was heated at 80C for 4 hours. The progress of the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was adsorbed on celite and purified by silica gel column chromatography using Heptane/EtOAc as eluent. Fractions containing the product Z were collected, concentrated under reduced pressure, and redissolved in 2 mL of dichloromethane. To this solution, 2 mL of TFA was added, and reaction mixture was stirred at room temperature for several hours (6-12 h.). The progress of the reaction was monitored by LCMS. After the reaction reached maximum conversion, all volatiles were removed under reduced pressure, and the residue was co-evaporated with toluene (2 x 30 mL) to remove the traces of TFA. The cmde product was redissolved in dichloromethane (15 mL). Carbonyldiimidazole (100.9 mg, 0.622 mmol, 3 eq.) was added to the DCM solution, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a 0.1 M solution of hydrochloric acid (100 mL). Organic fractions were extracted with dichloromethane, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica gel column and purified using dichloromethane/methanol as eluent, providing the desired compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.5% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 98℃; for 24h;Inert atmosphere; | Step A:<strong>[88982-82-5]4-bromothiazole-2-carboxylic acid</strong> (1,1.0 g, 4.8 mmol)Dissolved in ethylene glycol dimethyl ether (12mL)And water (4mL),Add 2-chloro-5-pyridineboronic acid (21, 1.1 g, 7.2 mmol)And anhydrous potassium carbonate (994 mg, 7.2 mmol),Then tetrakis(triphenylphosphine)palladium (277 mg, 0.24 mmol) was added.The resulting mixture was stirred at 98 C for 24 hours under a nitrogen atmosphere.TLC analysis indicated that the reaction was over,The reaction solution was cooled to room temperature.Then add water (40 mL),The pH was adjusted to 2-3 with 6M hydrochloric acid.Filtered, the filter cake was dissolved in 20 mL of dichloromethane.The dichloromethane layer was washed with a saturated sodium bicarbonate solution.Divide the water layer,Adjust the pH of the water layer to 2-3,Filter the suspension,The filter cake was dried to give compound 22 (987 mg).Yield: 85.5%. |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24h;Inert atmosphere; | General procedure: 4-Bromothiazole-2-carboxylic acid (compound 1, 1 eq) and boronic acid derivatives (compound 2a-g, 1.5 eq) were suspended in dimethoxy ethane (DME)/H2O (16 volume, 3:1). Then, Pd(PPh3)4 (0.05 eq) and K2CO3 (1.5 eq) were added to the suspension. The obtained mixture was heated to about 100 C and stirred for about 24 h under nitrogen atmosphere. The solution was cooled to room temperature and acidified with concentrated hydrochloric acid. Then, the precipitate was filtered and washed with water. The obtained wet cake was redissolved in dichloromethane. The organic phase was washed with saturated sodium bicarbonate (NaHCO3) aqueous solution for 30 min. Then, the aqueous phase was acidified again with concentrated hydrochloric acid, and the precipitate was filtered to obtained compounds 3a-g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; water; at 60℃;Inert atmosphere; | General procedure: The TBS protected steroid triflate 722 or 1224 (1.00 equiv.), cesiumcarbonate (2.00 equiv.) and the boronic acid (1.05 equiv.) was individuallyplaced in a flame dried 10 mL round bottomed flask anddissolved in a 1:1 mixture of water and THF (6.00-8.00 mL). Then Pd(PPh3)4 (5 mol %) was added and the reaction mixture was stirred at60 C under argon atmosphere overnight. The reaction mixture wasthen brought to room temperature, added brine (10 mL) and extractedwith ethyl acetate (4×5.00 mL). The combined organic phases weredried over MgSO4 and evaporated in vacuo. The residue was purified byflash column chromatography (silica gel, 10-20% EtOAc in heptane) toobtain the pure TBS-ethers of 9a-9e or 13a-13b as light yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; water; at 60℃;Inert atmosphere; | General procedure: The TBS protected steroid triflate 722 or 1224 (1.00 equiv.), cesiumcarbonate (2.00 equiv.) and the boronic acid (1.05 equiv.) was individuallyplaced in a flame dried 10 mL round bottomed flask anddissolved in a 1:1 mixture of water and THF (6.00-8.00 mL). Then Pd(PPh3)4 (5 mol %) was added and the reaction mixture was stirred at60 C under argon atmosphere overnight. The reaction mixture wasthen brought to room temperature, added brine (10 mL) and extractedwith ethyl acetate (4×5.00 mL). The combined organic phases weredried over MgSO4 and evaporated in vacuo. The residue was purified byflash column chromatography (silica gel, 10-20% EtOAc in heptane) toobtain the pure TBS-ethers of 9a-9e or 13a-13b as light yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With oxygen; copper diacetate; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 6h; | General procedure: To a solution of <strong>[461-89-2]6-azauracil</strong> (100 mg, 0.88 mmol) inDMF (10.0 mL) was added base (1.76 mmol) and Cu(OAc) 2(159 mg, 0.88 mmol) at room temperature. The resulting reationmixture was degassed with oxygen for 10 min and then addedarylboronic acids (0.96 mmol) at room temperature and stirredat appropriate temperature (Table-1) under oxygen atmosphere.The reaction mixture was diluted with water (15 mL) andextracted with dichloromethane (3 × 15 mL). The organic layerwashed with H 2 O (15 mL), brine solution (15 mL), dried overNa 2 SO 4 and concentrated. The obtained crude product waspurified by column chromatography (0 to 10 % CH 3 OH/CH 2 Cl 2 )to afford the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃;Inert atmosphere; | General procedure: In a dried MW flask under Ar were introduced arylbromide (1 eq.), Na2CO3 (3 eq.) and arylboronic acid (1.2 eq.) followed by the addition of toluene/ EtOH/H2O (4/1/1: C: 0.2 mmol/mL). The flask was purged three times with Ar before the addition of Pd(PPh3)4 (0.1 eq.). The flask was sealed and the reaction mixture was stirred overnight at 90 C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃;Inert atmosphere; | General procedure: In a dried MW flask under Ar were introduced arylbromide (1 eq.), Na2CO3 (3 eq.) and arylboronic acid (1.2 eq.) followed by the addition of toluene/ EtOH/H2O (4/1/1: C: 0.2 mmol/mL). The flask was purged three times with Ar before the addition of Pd(PPh3)4 (0.1 eq.). The flask was sealed and the reaction mixture was stirred overnight at 90 C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃;Inert atmosphere; | General procedure: In a dried MW flask under Ar were introduced arylbromide (1 eq.), Na2CO3 (3 eq.) and arylboronic acid (1.2 eq.) followed by the addition of toluene/ EtOH/H2O (4/1/1: C: 0.2 mmol/mL). The flask was purged three times with Ar before the addition of Pd(PPh3)4 (0.1 eq.). The flask was sealed and the reaction mixture was stirred overnight at 90 C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
860 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 10h;Inert atmosphere; | In step (a), 1-bromo 3,5-bis (trifluoromethyl) benzene (compound a, 1.10 mL, 6.35 mmol) and tetrakis (triphenylphosphine) palladium (0) (0 , 187 mg, 0.162 mmol) was dissolved in 1,2-dimethoxyethane under a nitrogen atmosphere and stirred at room temperature for 1 hour, which was designated as solution A. Thereafter, in a separate flask, (2-chloro-4-pyridyl) boronic acid (compound b, 1.0 g, 6.35 mmol) and sodium carbonate (1.21 g, 10.7 mmol) were dissolved in 10 mL of ion- While stirring, nitrogen flow was carried out for about 1 hour to replace oxygen in the ion exchanged water, and this solution was designated as solution B. Then, to the flask containing the solution A, the solution B was dropped with a pipette and mixed, and the mixture was heated at about 100 C. for 10 hours under nitrogen. After cooling to room temperature, the organic layer was concentrated under reduced pressure and filtered to obtain a white solid. The solid was dried and purified with a silica column using chloroform as a developing solvent to obtain about 860 mg of a white solid. This was designated Compound 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.1% | With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; sodium carbonate; In water; N,N-dimethyl-formamide; for 24h;Reflux; | General procedure: To a stirred solution of 5-bromotetrandrine (70 mg, 0.100 mmol) in the mixture of tolueneor dimethyl formamide (DMF) or 1,4-dioxane and water (25 ml, 5:1, v/v) was addedsodium carbonate (aq, 5 ml, 1 M) and the resulting mixture was degassed ultrasonicallyat room temperature for 20 min. Tetrabutylammonium bromide (Tbab) (64.4 mg,0.200 mmol), a boronic acid derivative (0.200 mmol) and pd(pph3)4 (34.6 mg, 0.030 mmol) were successively added to the mixture under a nitrogen or carbon dioxide atmosphere.The mixture was then heated to reflux for 24 h before being quenched with ice water (5 ml).The reaction mixture was extracted with ethyl acetate (2 × 15 ml). The combined organicextracts were washed with saturated sodium chloride solution (3 × 30 ml), and dried overanhydrous sodium sulfate. Removal of solvent followed by purification by preparative thinlayer chromatography (eluent: dichloromethane-methanol-ethyl acetate-petroleum ether,15:1:1:1, v/v/v/v) afforded the final products Y1~Y15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.7% | (2-Chloro-4-pyridyl)boronic acid (64 mg, 0.407 mmol) was added to a solution of 6-(difluoromethyl)-3-iodo-imidazo[1,2-b]pyridazine (100 mg, 0.339 mmol), 1,1'- bis(diphenylphosphino)ferrocene palladium(II)chloride dichloromethane complex (27.7 mg, 0.034 mmol) and Na2CO3 (508.5 muL of 2 M, 1.017 mmol) in 1,4-dioxane (6 mL) and the mixture was heated at 70 C for 16 hours. After cooling to ambient temperature, 2-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethanol (40.4 mg, 0.169 mmol) was added to the mixture, followed by Pd(PPh3)4 (19.6 mg, 0.017 mmol). The mixture was heated in a microwave for 30 minutes at 140 C, then concentrated in vacuo and the residue purified by reverse phase chromatography (C18, MeCN / water / 0.05% TFA as eluent) to give 2-(4-(4-(6- (difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1H-pyrazol-1-yl)ethanol (4.5 mg, 3.7% |
[ 1072951-54-2 ]
(2,6-Dichloropyridin-4-yl)boronic acid
Similarity: 0.84
[ 1003043-40-0 ]
(6-Chloro-5-methylpyridin-3-yl)boronic acid
Similarity: 0.73
[ 861905-97-7 ]
(2-Methylpyridin-4-yl)boronic acid hydrochloride
Similarity: 0.72
[ 458532-84-8 ]
2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
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[ 1072951-54-2 ]
(2,6-Dichloropyridin-4-yl)boronic acid
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[ 1003043-40-0 ]
(6-Chloro-5-methylpyridin-3-yl)boronic acid
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[ 458532-84-8 ]
2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
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[ 1070893-11-6 ]
(4,6-Dichloropyridine-3yl)boronic acid
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[ 148493-34-9 ]
2,6-Dichloropyridin-3-ylboronic acid
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[ 1072951-54-2 ]
(2,6-Dichloropyridin-4-yl)boronic acid
Similarity: 0.84
[ 1003043-40-0 ]
(6-Chloro-5-methylpyridin-3-yl)boronic acid
Similarity: 0.73
[ 861905-97-7 ]
(2-Methylpyridin-4-yl)boronic acid hydrochloride
Similarity: 0.72
[ 458532-84-8 ]
2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
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P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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