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CAS No. : | 1328893-16-8 | MDL No. : | MFCD21605341 |
Formula : | C4H3BrN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 190.98 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 33.25 |
TPSA : | 65.98 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) : | -6.68 cm/s |
Log Po/w (iLOGP) : | 0.29 |
Log Po/w (XLOGP3) : | 1.1 |
Log Po/w (WLOGP) : | 0.87 |
Log Po/w (MLOGP) : | 0.06 |
Log Po/w (SILICOS-IT) : | 1.15 |
Consensus Log Po/w : | 0.69 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.06 |
Solubility : | 1.65 mg/ml ; 0.00867 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.08 |
Solubility : | 1.59 mg/ml ; 0.00835 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.46 |
Solubility : | 6.56 mg/ml ; 0.0344 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.79 |
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 |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 5-bromo-1H-pyrazole-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.333333h; Stage #2: (S)-3-amino-N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-2-methylpropanamide In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; | I.5 Preparation of (S)-5-bromo-N-(3-(4-cyano-3-trifluoromethyl-phenyl)-amino)-2-hydroxy-2-methyl-3-oxopropyl)- 1H-pyrazole-3-carboxamide (C16H13BrF3N5O3) Add in 100mL round bottom flask5-bromo-1H-pyrazole-3-carboxylic acid (0.16 g, 0.8355 mmol), 1.5 mL anhydrousDMF was used as a solvent, and EDCI (0.16 g, 1.0444 mmol), DIPEA (0.24 mL, 1.3926 mmol) and HOBT (32 mg, 0.2089 mmol) were added and stirred for 20 minutes.Add another starting material (S)-3-amino-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) A solution of 4.0 mL of anhydrous DMF was then stirred at room temperature for 3 days under argon.After confirming the completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to obtain Oily substance. Separation by silica gel column chromatography (mobile phase: methylene chloride:methanol = 9:1). Purified to obtain 0.176 g of pale yellow powder. The yield was about 55.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In ethanol for 12h; Reflux; | 1.S6; 2.S6; 3.S6 S6. Dissolve 5-bromo-1H-3-pyrazolecarboxylic acid and 2,3-dichloropyridine in ethanol solution, and then add potassium carbonate solid. After heating and refluxing, 1-(3-chloro-2-pyridyl)-3-bromo-1H-5-pyrazolecarboxylic acid is obtained. In this condensation reaction, the heating and refluxing reaction time needs to be controlled to 12h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-amino-3-methyl-5-chlorobenzoic acid methyl ester at 80℃; for 0.583333h; | 1.S5; 2.S5; 3.S5 S5. Add 3-methyl-5-bromopyrazole to methyl 5-chloro-3-methyl-2-aminobenzoate an oxidant for oxidation reaction. The reaction temperature needs to be controlled to 80 °C, and the reaction time of stirring is controlled to 35min, 5-bromo-1H-3-pyrazolecarboxylic acid is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 120℃; for 19h; Inert atmosphere; | 5-(5-bromo-1H-pyrazol-3-yl)-3-phenyl-1,2,4-oxadiazole (63) To a stirred solution of carboxylic acid 60 (121 mg; 0.63 mmol) in anhydrousTHF (5 mL), EDC.HCl (121 mg; 0.63 mmol) and HOBt.H2O (106mg; 0.69 mmol) were subsequently added under Ar. DIPEA (219 μL;1.26 mmol) was dropwise added followed by benzamidoxime (86 mg;0.63 mmol). The reaction mixture was stirred overnight (16 h) until fullconsumption of SC monitored by TLC. The reaction was then heated to120 C till complete formation of cyclic product 63 (3 h). The mixturewas concentrated and the resulting residue was purified by columnchromatography using mobile phase petroleum ether (PE)/EA (3:1) toget final product 63 as a white solid. Yield 50% after two steps from estercompound 51. 1H NMR (500 MHz, DMSO-d6) δ 14.63 (bs, 1H),8.12-8.02 (m, 2H), 7.67-7.54 (m, 3H), 7.30 (s, 1H). HRMS (ESI+):[M+H]+: calculated for C11H8BrN4O+ (m/z): 290.98760; detected:290.98718. | |
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 120℃; for 19h; Inert atmosphere; | 5-(5-bromo-1H-pyrazol-3-yl)-3-phenyl-1,2,4-oxadiazole (63) To a stirred solution of carboxylic acid 60 (121 mg; 0.63 mmol) in anhydrousTHF (5 mL), EDC.HCl (121 mg; 0.63 mmol) and HOBt.H2O (106mg; 0.69 mmol) were subsequently added under Ar. DIPEA (219 μL;1.26 mmol) was dropwise added followed by benzamidoxime (86 mg;0.63 mmol). The reaction mixture was stirred overnight (16 h) until fullconsumption of SC monitored by TLC. The reaction was then heated to120 C till complete formation of cyclic product 63 (3 h). The mixturewas concentrated and the resulting residue was purified by columnchromatography using mobile phase petroleum ether (PE)/EA (3:1) toget final product 63 as a white solid. Yield 50% after two steps from estercompound 51. 1H NMR (500 MHz, DMSO-d6) δ 14.63 (bs, 1H),8.12-8.02 (m, 2H), 7.67-7.54 (m, 3H), 7.30 (s, 1H). HRMS (ESI+):[M+H]+: calculated for C11H8BrN4O+ (m/z): 290.98760; detected:290.98718. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-bromo-1H-pyrazole-3-carboxylic acid; benzoic acid hydrazide With dibromotriphenylphosphorane In acetonitrile at 20℃; for 1h; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 2h; | 2-(5-bromo-1H-pyrazol-3-yl)-5-phenyl-1,3,4-oxadiazole (64) General procedure: Prepared according to described procedure [17]. To a stirred suspensionof carboxylic acid 60 (83 mg; 0.43 mmol) and benzhydrazide (59 mg;0.43 mmol) in anhydrous acetonitrile (MeCN; 5 mL); triphenylphosphinodibromide (PPh3Br2; 886 mg; 2.1 mmol) was added and the reactionmixture was stirred at RT for an hour. Then, reaction mixture wascooled to 0 C and DIPEA (383 μL, 2.2 mmol) was added and the reactionwas stirred for another 2 h. MeCN was removed by rotary evaporatorand the residue was diluted by H2O (30 mL) and EA (30 mL). Aqueousphase was three times extracted with EA (3 × 30 mL). The organic layerswere collected, dried over anhydrous Na2SO4 and filtered. The filtratewas concentrated under reduced pressure and the resulting residue waspurified by column chromatography using mobile phase PE/EA (3:1) toget final product 64 as white solid. Yield 50% after two steps from estercompound 51. 1H NMR (500 MHz, DMSO-d6) δ 14.83-14.24 (m, 1H),8.15-8.05 (m, 2H), 7.71-7.59 (m, 3H), 7.22 (s, 1H). HRMS (ESI+):[M+H]+: calculated for C11H8BrN4O+ (m/z): 290.98760; detected:290.98758. | |
Stage #1: 5-bromo-1H-pyrazole-3-carboxylic acid; benzoic acid hydrazide With dibromotriphenylphosphorane In acetonitrile at 20℃; for 1h; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 2h; | 2-(5-bromo-1H-pyrazol-3-yl)-5-phenyl-1,3,4-oxadiazole (64) General procedure: Prepared according to described procedure [17]. To a stirred suspensionof carboxylic acid 60 (83 mg; 0.43 mmol) and benzhydrazide (59 mg;0.43 mmol) in anhydrous acetonitrile (MeCN; 5 mL); triphenylphosphinodibromide (PPh3Br2; 886 mg; 2.1 mmol) was added and the reactionmixture was stirred at RT for an hour. Then, reaction mixture wascooled to 0 C and DIPEA (383 μL, 2.2 mmol) was added and the reactionwas stirred for another 2 h. MeCN was removed by rotary evaporatorand the residue was diluted by H2O (30 mL) and EA (30 mL). Aqueousphase was three times extracted with EA (3 × 30 mL). The organic layerswere collected, dried over anhydrous Na2SO4 and filtered. The filtratewas concentrated under reduced pressure and the resulting residue waspurified by column chromatography using mobile phase PE/EA (3:1) toget final product 64 as white solid. Yield 50% after two steps from estercompound 51. 1H NMR (500 MHz, DMSO-d6) δ 14.83-14.24 (m, 1H),8.15-8.05 (m, 2H), 7.71-7.59 (m, 3H), 7.22 (s, 1H). HRMS (ESI+):[M+H]+: calculated for C11H8BrN4O+ (m/z): 290.98760; detected:290.98758. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium hydroxide monohydrate In tetrahydrofuran at 100℃; for 2h; | 5.2.6. Preparation of pyrazole-3-yloxadiazole series General procedure: 5-bromo-1H-pyrazole-3-carboxylic acid (60): To a stirred solutionof compound 51 (913 mg; 4.45 mmol) in THF (15 mL), 2 M lithiumhydroxide solution (LiOH; 426 mg; 17.8 mmol) was added, the mixturewas heated to 100 C for 2 h till reaction completion monitored by TLC.After cooling to RT, THF was removed, and the aqueous residue wascarefully acidified by AcOH to pH ≈ 7. Aqueous phase was three timeswashed with EA (3 × 50 mL). The organic layers were collected, driedover anhydrous Na2SO4 and filtered. The filtrate was concentratedunder reduced pressure to get carboxylic acid 60 as a white solid withquantitative yields. 1H NMR (500 MHz, DMSO-d6) δ 14.15 (s, 1H), 13.54(bs, 1H), 6.87 (s, 1H). HRMS (ESI+): [M+H]+: calculated forC4H4BrN2O2+ (m/z): 190.94507; detected: 190.94492. LC-MS purity96%. |
100% | With lithium hydroxide monohydrate In tetrahydrofuran at 100℃; for 2h; | 5.2.6. Preparation of pyrazole-3-yloxadiazole series General procedure: 5-bromo-1H-pyrazole-3-carboxylic acid (60): To a stirred solutionof compound 51 (913 mg; 4.45 mmol) in THF (15 mL), 2 M lithiumhydroxide solution (LiOH; 426 mg; 17.8 mmol) was added, the mixturewas heated to 100 C for 2 h till reaction completion monitored by TLC.After cooling to RT, THF was removed, and the aqueous residue wascarefully acidified by AcOH to pH ≈ 7. Aqueous phase was three timeswashed with EA (3 × 50 mL). The organic layers were collected, driedover anhydrous Na2SO4 and filtered. The filtrate was concentratedunder reduced pressure to get carboxylic acid 60 as a white solid withquantitative yields. 1H NMR (500 MHz, DMSO-d6) δ 14.15 (s, 1H), 13.54(bs, 1H), 6.87 (s, 1H). HRMS (ESI+): [M+H]+: calculated forC4H4BrN2O2+ (m/z): 190.94507; detected: 190.94492. LC-MS purity96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.6 g | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 14h; | Intermediate 501. Methyl 1-(5-bromo-1H-pyrazole-3-carbonyl)piperidine-4- carboxylate EDCI (3.00 g, 15.71 mmol), HOBt (2.10 g, 15.71 mmol), and methyl piperidine-4- carboxylate (2.20 g, 15.71 mmol) were added to a stirred solution of 5-bromo-1H-pyrazole-3- carboxylic acid (2.00 g, 10.47 mmol) and DIPEA (7.28 mL, 41.89 mmol) in DMF (10.00 mL). The resulting mixture was stirred at 25 °C for 14 h. The mixture was then diluted with EtOAc, washed with water, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 1/1 v/v) to obtain the title compound (2.60 g) as an oil. LCMS (ESI): 316.0 [M+H]+. |
2.6 g | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 14h; | Intermediate 501. Methyl 1-(5-bromo-1H-pyrazole-3-carbonyl)piperidine-4- carboxylate EDCI (3.00 g, 15.71 mmol), HOBt (2.10 g, 15.71 mmol), and methyl piperidine-4- carboxylate (2.20 g, 15.71 mmol) were added to a stirred solution of 5-bromo-1H-pyrazole-3- carboxylic acid (2.00 g, 10.47 mmol) and DIPEA (7.28 mL, 41.89 mmol) in DMF (10.00 mL). The resulting mixture was stirred at 25 °C for 14 h. The mixture was then diluted with EtOAc, washed with water, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 1/1 v/v) to obtain the title compound (2.60 g) as an oil. LCMS (ESI): 316.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 g | With hatu; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 2h; | Step-1, tert-butyl 1-(5-bromo-1H-pyrazole-3-carbonyl)piperidine-4-carboxylate HATU (14.33 g, 37.70 mmol) and tert-butyl piperidine-4-carboxylate (8.73 g, 47.12 mmol) were added to a stirred mixture of 5-bromo-1H-pyrazolc-3-carboxylic acid (6.00 g, 31.42 mmol) and DIPEA (12.18 g, 94.24 mmol) in DMF (100.00 mL). The resulting mixture was stirred at 25 °C for 2 h. The solution was then diluted with water and extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 1/1 v/v) to obtain the title compound (8.00 g) as a solid. LCMS (ESI): 358.1 [M+H]+. |
8 g | With hatu; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 2h; | Step-1, tert-butyl 1-(5-bromo-1H-pyrazole-3-carbonyl)piperidine-4-carboxylate HATU (14.33 g, 37.70 mmol) and tert-butyl piperidine-4-carboxylate (8.73 g, 47.12 mmol) were added to a stirred mixture of 5-bromo-1H-pyrazolc-3-carboxylic acid (6.00 g, 31.42 mmol) and DIPEA (12.18 g, 94.24 mmol) in DMF (100.00 mL). The resulting mixture was stirred at 25 °C for 2 h. The solution was then diluted with water and extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether, 1/1 v/v) to obtain the title compound (8.00 g) as a solid. LCMS (ESI): 358.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.7 g | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 14h; | 101.1 Step-1. Ethyl 1-(5-bromo-1H-pyrazole-3-carbonyl)piperidine-4-carboxylate EDCI (6.13 g, 31.99 mmol), HOBt (4.32 g, 31.99 mmol), and ethyl piperidine-4- carboxylate (4.24 g, 27.07 mmol) were added to a stirred solution of 5-bromo-1H-pyrazole-3- carboxylic acid (4.7 g, 24.61 mmol) and DIPEA (12.9 mL, 73.83 mmol) in DMF (40 mL). The resulting mixture was stirred at 25 °C for 14 h, then diluted with EtOAc and washed with water. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 1/1 v/v) to obtain the title compound (7.7 g) as a solid. LCMS (ESI): 330.1 [M+H]+. |
7.7 g | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 14h; | 101.1 Step-1. Ethyl 1-(5-bromo-1H-pyrazole-3-carbonyl)piperidine-4-carboxylate EDCI (6.13 g, 31.99 mmol), HOBt (4.32 g, 31.99 mmol), and ethyl piperidine-4- carboxylate (4.24 g, 27.07 mmol) were added to a stirred solution of 5-bromo-1H-pyrazole-3- carboxylic acid (4.7 g, 24.61 mmol) and DIPEA (12.9 mL, 73.83 mmol) in DMF (40 mL). The resulting mixture was stirred at 25 °C for 14 h, then diluted with EtOAc and washed with water. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 1/1 v/v) to obtain the title compound (7.7 g) as a solid. LCMS (ESI): 330.1 [M+H]+. |
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