Structure of 89607-15-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 89607-15-8 |
Formula : | C4H4BrN3O2 |
M.W : | 206.00 |
SMILES Code : | O=[N+](C1=CN(C)N=C1Br)[O-] |
MDL No. : | MFCD00466335 |
InChI Key : | BHFRSRAZJCLLDY-UHFFFAOYSA-N |
Pubchem ID : | 13185127 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 40.01 |
TPSA ? Topological Polar Surface Area: Calculated from |
63.64 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.3 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.09 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.52 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.94 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.61 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.11 |
Solubility | 1.61 mg/ml ; 0.0078 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.02 |
Solubility | 1.97 mg/ml ; 0.00958 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.04 |
Solubility | 19.0 mg/ml ; 0.092 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.78 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.03 |
* 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 tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 25℃; for 2h; | Step 4: Into a 250 mL round bottom flask containing a solution of copper(II) bromide (3.0 g, 14 mmol) and tert-butyl nitrite (1.7 mL, 14 mmol) in acetonitrile (150 mL) was added 1-methyl-4- nitro-1H-pyrazol-3-amine (2 g, 14 mmol) in acetonitrile (20 mL) at 0 C and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (120 mL), washed with water and brine,dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with ethyl acetate in petroleum ether(20-30%) to afford 3-bromo-1-methyl-4-nitro-1H-pyrazole as a solid. ?H NMR (CDC13, 300MHz): 5 8.25 (s, 1H), 3.89 (s, 3H). | |
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 25℃; for 2.08333h; | Step 3: A mixture of copper(II) bromide (5.5 g, 25 mmol) and tert-butyl nitrite (2.5 g, 25 mmol) in acetonitrile (100 mL) was taken into a 250 mL round bottom flask and cooled to 0 C. Asolution of 1-methyl-4-nitro-1H-pyrazol-3-amine (3.5 g, 25 mmol) in acetonitrile (20 mL) was added dropwise over a period of 5 mm. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (15-20%) to afford 3-bromo-1-methyl-4-nitro-1H-pyrazole as a solid. ?H NMR (DM50-cl6, 400 MHz): 8.94 (s, 1H), 3.89 (s, 3H). | |
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 2h; | Stpe 4: Into a 250 mL round bottom flask containing a solution of copper(II) bromide (3.0 g, 14 mmol) and fert-butyl nitrite (1.7 mL, 14 mmol) in acetonitrile (150 mL) was added l-methyl-4- nitro-lH-pyrazol-3-amine (2 g, 14 mmol) in acetonitrile (20 mL) at 0 C and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (120 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (20-30%) to afford 3-bromo-l-methyl-4-nitro-lH-pyrazole as a solid. NMR (CDC13, 300 MHz): delta 8.25 (s, 1H), 3.89 (s, 3H). |
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 2h; | Step 4: Into a 250 mL round bottom flask containing a solution of copper(II) bromide (3.0 g, 14 mmol) and tert-butyl nitrite (1.7 mL, 14 mmol) in acetonitrile (150 mL) was added 1-methyl-4- nitro-1H-pyrazol-3-amine (2 g, 14 mmol) in acetonitrile (20 mL) at 0 oC and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (120 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (20-30%) to afford 3-bromo-1-methyl-4-nitro-1H-pyrazole as a solid. 1H NMR (CDCl3, 300 MHz): delta 8.25 (s, 1H), 3.89 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; In ethyl acetate; at 25℃; for 16h; | Step 5: Into a 100 mL round bottom flask containing a solution of <strong>[89607-15-8]3-bromo-1-methyl-4-nitro-1H-pyrazole</strong> (1.0 g) in ethyl acetate (50 mL) at room temperature was added Raney Nickel (700mg) and the reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (40-50%) to afford 3-bromo-1-methyl-1H-pyrazol- 4-amine as a liquid. ?H NMR (CD3OD, 400 MHz): 5 7.18 (s, 1H), 3.77 (s, 3H). MS calc?d [M+Hj 176.0, found 176.2. | |
With hydrogen; In ethyl acetate; at 25℃; for 16h; | Step 5: Into a 100 mL round bottom flask containing a solution of <strong>[89607-15-8]3-bromo-1-methyl-4-nitro-1H-pyrazole</strong> (1.0 g) in ethyl acetate (50 mL) at room temperature was added Raney Nickel (700mg) and the reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (40-50%) to afford 3-bromo-1-methyl-1H-pyrazol- 4-amine as a liquid. ?H NMR (CD3OD, 400 MHz): 7.18 (s, 1H), 3.77 (s, 3H). MS calc?d[M+Hj 176.0, found 176.2. | |
With hydrogen; In ethyl acetate; at 20℃; for 16h; | Stpe 5: Into a 100 mL round bottom flask containing a solution of 3-bromo-l-methyl-4-nitro- lH-pyrazole (1.0 g) in ethyl acetate (50 mL) at room temperature was added Raney Nickel (700 mg) and the reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (40-50%) to afford 3-bromo-l -methyl- lH-pyrazol- 4-amine as a liquid. 1 NMR (CD3OD, 400 MHz): delta 7.18 (s, 1H), 3.77 (s, 3H). MS calc'd [M+H]+ 176.0, found 176.2. |
With hydrogen; In ethyl acetate; at 20℃; for 16h; | Step 5: Into a 100 mL round bottom flask containing a solution of 3-bromo-1-methyl-4-nitro- 1H-pyrazole (1.0 g) in ethyl acetate (50 mL) at room temperature was added Raney Nickel (700 mg) and the reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (40-50%) to afford 3-bromo-1-methyl-1H-pyrazol-4-amine as a liquid. 1H NMR (CD3OD, 400 MHz): delta 7.18 (s, 1H), 3.77 (s, 3H). MS calc?d [M+H]+ 176.0, found 176.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 120℃; for 6h; | Step 4: Into a 25 mL round bottom flask containing a solution of 3-bromo-1-methyl-4-nitro-1H- pyrazole (1.0 g, 5 mmol) in toluene (5 mL) were added tributyl(vinyl)tin (1.7 mL, 58 mmol) andtetrakis(triphenylphosphine)palladium(0) (300 mg, 0.25 mmol) and the reaction was heated at120 C for 6 h. The reaction mixture was cooled to room temperature, concentrated and purifiedby flash chromatography eluting with ethyl acetate in petroleum ether (15-20%) to afford 1-methyl-4-nitro-3-vinyl-1H-pyrazole as a solid. ?H NMR (CDC13, 300 MHz): 8.07 (s, 1H), 7.22(dd,J= 17.6, 11.2 Hz, 1H), 6.19 (dd,J= 17.7, 4.6 Hz, 1H), 5.54(dd,J= 11.1, 1.6 Hz, 1H), 3.97(s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 14h;Sealed tube; Inert atmosphere; | Step 1: Into a 10 mL sealed tube containing a solution of 3-bromo-1-methyl-4-nitro-JH-pyrazole (800 mg, 0.4 mmol) in 1,4-dioxane (2 mL) were added potassium phosphate tribasic (140 mg,0.7 mmol) in water (1 mL) and pyridin-4-ylboronic acid (70 mg, 0.6 mmol) and the mixture was degassed with nitrogen for 10 mm. [1,1?-bis(diphenylphosphino)ferrocenej dichloropalladium(II),complex with dichloromethane (20 mg, 0.03 mmol) was added and the reaction mixture was heated at 80 C for 14 h. The reaction mixture was filtered thorugh celite and the filterate was concentrated under reduced pressure.The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (10-15%) to yield 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyridine. ?H NMR (DMSO-d6, 300 MHz): oe 8.98 (s, 1H), 8.67 (d, J 6.1 Hz, 2H), 7.62 (d, J 6.1 Hz, 2H), 3.95 (s, 3H). MS calc?d [M+Hj 205.1, found 205.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 25℃; for 2h; | To a mixture of 3-bromo-4-nitro-1H-pyrazole (6.20 g, 32.3 mmol) and K2CO3 (5.36 g, 38.7 mmol) in DMF (40 mL) was added MeI (5.50 g, 38.7 mmol) at 0 C. Then, the mixture was stirred at 25 C. for 2 hours. On completion, the mixture was diluted with water (200 mL), then extracted with EA (3×80 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (PE:EA=20:1-3:1) to give the title compound (3.90 g, 58% yield) as light yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.16 (s, 1H), 3.97 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; dichloromethane; water; at 80℃; for 2h;Inert atmosphere; | A mixture of 3-bromo-1-methyl-4-nitro-pyrazole (3.80 g, 18.4 mmol), (5-methoxycarbonyl-3-pyridyl)boronic acid (4.67 g, 25.8 mmol, CAS871329-53-2), Pd(dppf)Cl2.CH2Cl2 (800 mg, 979 umol) and NaHCO3 (3.10 g, 36.8 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 80 C. under N2 for 2 hours. On completion, the mixture was cooled to 25 C. The mixture was diluted with water (100 mL), then extracted with EA (3×80 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA=5:1-DCM:EA=2:1) to give the title compound (2.95 g, 61% yield) as light yellow solid. 1H NMR (400 MHz, CDCl3) delta 9.29 (s, 1H), 9.12 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 4.05 (s, 3H), 4.00 (s, 3H). |
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