Structure of 1188265-60-2
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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. : | 1188265-60-2 |
| Formula : | C6H9BrClN3 |
| M.W : | 238.51 |
| SMILES Code : | BrC1=NC=C2CNCCN21.[H]Cl |
| English Name : | 3-Bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride |
| MDL No. : | MFCD13152217 |
| InChI Key : | FNKYKFZYHXJZRI-UHFFFAOYSA-N |
| Pubchem ID : | 72206755 |
| Num. heavy atoms | 11 |
| Num. arom. heavy atoms | 5 |
| Fraction Csp3 | 0.5 |
| Num. rotatable bonds | 0 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 52.53 |
| TPSA ? Topological Polar Surface Area: Calculated from |
29.85 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.95 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.02 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.55 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.19 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.74 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.25 |
| Solubility | 1.33 mg/ml ; 0.00558 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.16 |
| Solubility | 16.4 mg/ml ; 0.0686 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.15 |
| Solubility | 1.69 mg/ml ; 0.0071 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) |
Yes |
| 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 |
-7.08 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 |
0.0 |
| 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 |
0.0 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) |
2.44 |
* 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 |
|---|---|---|
| 51% | With tripotassium phosphate tribasic; methanesulfonato (2-dicyclohexylphosphino-2’,6’- di-isopropoxy-1,1‘-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl)palladium(II) In 1,4-dioxane at 95℃; for 20h; Inert atmosphere; | 2.2 4-(3-Bromo-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-3-fluorobenzonitrile 2c Compound 2b (220 mg, 1.02 mmol), 4-bromo-3-fluorobenzonitrile (409 mg, 2.05 mmol), potassium phosphate (868 mg, 4.09 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G3) (128 mg, 0.153 mmol) , dissolved in dioxane (8 mL), purged with nitrogen three times, stirred at room temperature for 10 minutes, and then heated to 95°C for 20 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using Purification by column chromatography with eluent system A afforded the title compound 2c (170 mg, yield: 51%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride In 1,4-dioxane; methanol; dichloromethane at 20℃; for 4h; Cooling with ice; | 2.1 3-Bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride 2b tert-butyl 3-Bromo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate 2a (1.0 g, 3.31 mmol) was dissolved in a mixture of dichloromethane and methanol solution (12 mL, V/V=1:1). Under an ice bath, 4M hydrogen chloride solution in dioxane (12 mL) was added, and the reaction was slowly returned to room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 2b, and the crude product was directly used in the next reaction. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1: tripotassium phosphate tribasic; methanesulfonato (2-dicyclohexylphosphino-2’,6’- di-isopropoxy-1,1‘-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl)palladium(II) / 1,4-dioxane / 20 h / 95 °C / Inert atmosphere 2: anhydrous sodium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / lithium hydroxide monohydrate; 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 3: sodium tetrahydridoborate / tetrahydrofuran / 0.5 h / Cooling with ice 4: triphenylphosphine; carbon tetrabromide / dichloromethane / 1 h 5: potassium carbonate / N,N-dimethyl-formamide / 1 h 6: benzenesulfonic acid / acetonitrile / 16 h / 80 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1: tripotassium phosphate tribasic; methanesulfonato (2-dicyclohexylphosphino-2’,6’- di-isopropoxy-1,1‘-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl)palladium(II) / 1,4-dioxane / 20 h / 95 °C / Inert atmosphere 2: anhydrous sodium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / lithium hydroxide monohydrate; 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 3: sodium tetrahydridoborate / tetrahydrofuran / 0.5 h / Cooling with ice 4: triphenylphosphine; carbon tetrabromide / dichloromethane / 1 h 5: potassium carbonate / N,N-dimethyl-formamide / 1 h |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: tripotassium phosphate tribasic; methanesulfonato (2-dicyclohexylphosphino-2’,6’- di-isopropoxy-1,1‘-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl)palladium(II) / 1,4-dioxane / 20 h / 95 °C / Inert atmosphere 2: anhydrous sodium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / lithium hydroxide monohydrate; 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 3: sodium tetrahydridoborate / tetrahydrofuran / 0.5 h / Cooling with ice |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: tripotassium phosphate tribasic; methanesulfonato (2-dicyclohexylphosphino-2’,6’- di-isopropoxy-1,1‘-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl)palladium(II) / 1,4-dioxane / 20 h / 95 °C / Inert atmosphere 2: anhydrous sodium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / lithium hydroxide monohydrate; 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 3: sodium tetrahydridoborate / tetrahydrofuran / 0.5 h / Cooling with ice 4: triphenylphosphine; carbon tetrabromide / dichloromethane / 1 h |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride; 4-Nitrophenyl chloroformate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Stage #2: 1-(difluoromethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole dihydrochloride In dichloromethane; N,N-dimethyl-formamide at 80℃; | 406.1 STEP-1: Synthesis of (3-bromo-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methanone To a mixture of 3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, HCl (239 mg, 1 mmol) and 4-nitrophenyl carbonochloridate (202 mg, 1.000 mmol) in CH2Cl2 (4 mL) at 0 °C was added slowly Hunig's base (0.43 mL, 2.5 mmol). The mixture was allowed to warm to rt and stirred for another 1 hr. The mixture was blowing down to give a crude mixture. To the crude mixture was added 1-(difluoromethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole, 2HCl (324 mg, 1.0 mmol), then DMF (3 ml) and Hunig's base (0.68 mL, 4 mmol). The mixture was heated at 80 °C for overnight. The mixture was diluted with EtOAc (30 mL) and washed with H2O (60 mL x 3). The organic layer was dried (Na2SO4) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 0-10-12% MeOH/EtOAc as the eluent to give (3-bromo-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methanone (ca.55% purity, 245 mg, 0.281 mmol, 28.1% yield). The product, ca.55% purity, contained impurity and was used for next step without further purification. LC-MS (Method 1): tR = 2.84 min, m/z (M+H)+= 481. |

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