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CAS No. : | 885276-93-7 | MDL No. : | MFCD06739182 |
Formula : | C10H9BrN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LJKZKCQPVABNLG-UHFFFAOYSA-N |
M.W : | 269.10 | Pubchem ID : | 53249841 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 58.98 |
TPSA : | 43.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.54 cm/s |
Log Po/w (iLOGP) : | 2.31 |
Log Po/w (XLOGP3) : | 1.97 |
Log Po/w (WLOGP) : | 2.27 |
Log Po/w (MLOGP) : | 2.31 |
Log Po/w (SILICOS-IT) : | 1.76 |
Consensus Log Po/w : | 2.13 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.0 |
Solubility : | 0.272 mg/ml ; 0.00101 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.51 |
Solubility : | 0.83 mg/ml ; 0.00308 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.42 |
Solubility : | 0.102 mg/ml ; 0.00038 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.9 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; | A solution of ethyl 5-bromopyrazolo[1,5-ajpyridine-3-carboxylate (1.0 g, 3.73 mmol),methylboronic acid (448 mg, 7.46 mmol), Pd(dppf)C12 (545 mg, 0.746 mmol) and C52CO3(2.42 g, 7.46 mmol) was dissolved in DMF (5.0 mL), then the mixture was stirred at 100 °Cfor two hours. It was concentrated, and purified by silica gel chromatography with PE:EA=5: 1to obtain the desired compound as an orange solid (589 mg, 77percent). ESI MS m/z = 204.5[M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.5% | at 100℃; for 4 h; | A solution of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (240 mg, 0.89 mmol) in 40percent H2SO4 (12 mL) was stirred at 100° C. for 4 hours, then cooled to rt, and neutralized to pH=7 with aq. NaOH (6 M) in ice bath. The resulted mixture was extracted with DCM (25 mL×2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a light yellow solid (175 mg, 99.5percent). MS (ESI, pos. ion) m/z: 196.9 [M+H]+. |
96% | Stage #1: for 18 h; Reflux Stage #2: With sodium hydroxide In water |
General procedure: These were made by decarboxylation/Vilsmeier or hydrolysis/reduction/reoxidation as detailed below, unless otherwise stated.Decarboxylation was carried out by refluxing a solution of the ester (1 equiv) in 40percent aqueous H2SO4 (3 mL) for 18 h. The solution was then cooled in ice and neutralised to pH 7 with 6 M NaOH, then extracted twice with CH2Cl2. The combined extracts were dried (Na2SO4) and the solvent removed in vacuo to leave the decarboxylated material. The pyrazolo[1,5-a]pyridine was then reacted under Vilsmeier conditions in dry DMF (2 mL) with POCl3 (3 equiv) at 0 °C under an atmosphere of N2. The reaction mixture was then warmed to room temperature and stirred for 2 h. The solution was poured onto ice, basified to pH 10 with 1 M NaOH, stirred for 1 h then extracted twice with CH2Cl2. The combined extracts were washed twice with water, dried (Na2SO4) and the solvent removed in vacuo to leave the aldehyde.Alternatively, the ester was hydrolysed by refluxing a solution of the ester (1 equiv) in 1 M NaOH (3 equiv) and EtOH (5 mL) for 6 h. The EtOH was removed in vacuo, and then the aqueous residue acidified to pH 1 with 1 M HCl. The precipitated carboxylic acid was filtered off, washed with water and dried. The carboxylic acid was reduced by adding CDI (1.5 equiv) to a suspension of carboxylic acid (1 equiv) in dry THF (10 mL) under an atmosphere of N2. After stirring for 18 h, the resulting solution was added dropwise to a solution of NaBH4 (5 equiv) in H2O (10 mL) and stirred for 30 min. The reaction was then quenched by the addition of 1 M HCl and stirred for a further 30 min. The solution was neutralised with saturated aqueous NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with a hexanes: EtOAc gradient) gave the alcohol. Reoxidation was carried out by stirring a suspension of the pyrazolo[1,5-a]pyridine-3-methanol (1 equiv) and MnO2 (10 equiv) in CH2Cl2 (2 mL) at room temperature for 4 days. The reaction mixture was then filtered through celite, washed with CH2Cl2, and the solvent removed from the filtrate in vacuo to leave the aldehyde. |
60% | With sulfuric acid In water at 110℃; for 16 h; | A suspension of ethyl 5-bromopyrazolo[1 ,5-a]pyridine-3-carboxylate 94-1 (1 .6 g, 5.94 mmol) in 70percent aq. H2S04 (15 mL) was maintained at 110 00 for 16 h. The reaction mixture was cooled to room temperature and poured into ice-cold water. The pH was adjusted to 7.0 using aq. 1 N NaOH solution, filtered the precipitated solid, washed with water, pet- ether and dried under vacuum to afford 700 mg (60percent) of 5-bromopyrazolo[1,5-a]pyridine 94-2 as an off white solid. ESI-LC/MS: m/z 196.74 (M+H) & 198.71 & [(M+2)+H]; R = 2.39 mm [Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEH 018, 1 .7 pm, 2.1 X 50mm column; gradient of 90:10 H20 (0.025percent TEA): CH3CN (0.025percent TEA) hold for 0.5 mm and to 10:90 H20 (0.025percent TEA) :CH3CN (0.025percent TEA) in 3.5 mm and hold for 1.5 mm with flow rate of 0.4 mL/min]. |
55% | at 80℃; | Compound 64.4. 5-BromopyrazoIo[l,5-a] pyridine. Into a 50-mL round-bottom flask, was placed ethyl 5-bromopyrazolo[l ,5-a]pyridine-3-carboxylate (compound 64.3, 100 mg, 0.37 mmol). Sulfuric acid (50percent, 4 mL) was added carefully in portions at room temperature, then the resulting solution was stirred overnight at 80 °C. After cooling to room temperature, the pH of the solution was carefully adjusted to 8-9 with aqueous sodium hydroxide (5 M) and then extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (40 mg, 55 |
55% | at 80℃; | Compound 64.4. 5-Bromopyrazolo[l,5-]pyridine. Into a 50-mL round-bottom flask, was placed ethyl 5-bromopyrazolo[l,5-a]pyridine-3-carboxylate (compound 64.3, 100 mg, 0.37 mmol). Sulfuric acid (50percent, 4 mL) was added carefully in portions at room temperature, then the resulting solution was stirred overnight at 80 °C. After cooling to room temperature, the pH of the solution was carefully adjusted to 8-9 with aqueous sodium hydroxide (5 M) and then extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (40 mg, 55 percent) |
550 mg | at 120℃; for 3 h; | A colorless mixture of A-13 (900.0 mg, 3.34 mmol) in H2504 (50percent,10.0 mL) was stirred at 120 °C for 3 hours. The mixture was diluted with ice-water, neutralizedwith solid Na2CO3 to pH = 7, and extracted with DCM (50 mL x 2). The combined organiclayers were washed with brine (10 mL), dried over Na2504, filtered and concentrated to affordA-14 (550.00 mg, 2.79 mmol) as an oil. ‘H NMR (400 MHz, CDC13) ö11 8.38 - 8.32 (m, 1H),7.95 (d, 1H), 7.72 (d, 1H), 6.83 (dd, 1H), 6.47 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 mg | With potassium carbonate In N,N-dimethyl-formamide for 0.166667 h; | Compound 64.3. Ethyl 5-bromopyrazolo[l,5-a]pyridine-3-carboxylate. Into a 250-mL three neck round-bottom flask, was placed a solution of l-amino-4-bromopyridin-l- ium iodide (compound 64.2, 15 g, -50percent purity, 24.9 mmol) in N.N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (1 1.7 mL, 1 15 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3 x 50 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (300 mg, 6percent). |
300 mg | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | Compound 64.3. Ethyl 5-bromopyrazolo[l,5-]pyridine-3-carboxylate. Into a 250-mL three neck round-bottom flask, was placed a solution of l-amino-4-bromopyridin-l- ium iodide (compound 64.2, 15 g, -50percent purity, 24.9 mmol) in N,N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (11.7 mL, 115 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3 x 50 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (300 mg, 6percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Stage #1: With mesitylenesulfonylhydroxylamine In N,N-dimethyl-formamide at 0 - 40℃; for 16 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 6 h; |
To a stirred solution of 4-bromopyridine (64.0 g, 40.5 mmol) in DME (200 mL) at 0 °0 was added O-(mesitylsulfonyl)hydroxylamine (80.0 g, 37.1 mmol) portion wise over a period of 20 mm. The resultant reaction mixture was allowed to warm to room temperature and maintained at 40°C for 16 h. The reaction mixture was cooled toO °0, diluted with DME (200 mL), K2003 (128 g, 92.7 mmol) followed by ethyl propiolate (43.07 mL, 42.5 mmol) were added and the resulting reaction mixture was stirred at rt for 6 h. The reaction mixture was poured on to ice-cold water, extracted with ethyl acetate (2 x 1000 mL). The ethyl acetate layer was washed with water, brine, dried over anhyd. Na2SO4 and concentrated. The crude compound was purified by column chromatography over silica gel (100—200 mesh) using a solvent gradient mixture of 7percent ethyl acetate in pet-ether to afford 3.5 g (3percent) of ethyl 5-bromopyrazolo[1 , 5-a]pyridine-3-carboxylate 94-1 as a light brown solid. ESI-LC/MS: m/z269.2 (M+H) & 271.2 [(M+2)+H]; R = 3.46 mm [Agilent [C with Ion trap Detector; Symmetry 018,3.5 pm, 4.6 X 75mm column; gradient of 50:50 H20 (0.1percent H000H): CH3CN (0.1percent H000H) to 10:90 H20 (0.1percent H000H):CH3CN (0.1percent H000H) in 4.0 mm and hold for 3.0 mm with flow rate of 1.0 mL/min]. |
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