Structure of 939412-86-9
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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. : | 939412-86-9 |
Formula : | C5H7Cl2N3 |
M.W : | 180.04 |
SMILES Code : | NCC1=NC=CN=C1Cl.[H]Cl |
MDL No. : | MFCD09910171 |
InChI Key : | YYVVOYJKQZWKFS-UHFFFAOYSA-N |
Pubchem ID : | 42614233 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 41.68 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.8 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 |
0.44 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.24 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.39 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.49 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.61 |
Solubility | 4.4 mg/ml ; 0.0245 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.1 |
Solubility | 14.4 mg/ml ; 0.0802 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.29 |
Solubility | 0.923 mg/ml ; 0.00513 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 |
-7.09 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 |
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) |
1.96 |
* 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 |
---|---|---|
84.4% | To a mixture of (3-chloropyrazin-2-yl)methanamine hydrochloride (3.9 g, 21.8 mmol, leq) and (S)-l-((benzyloxy)carbonyl)piperidine-2-carboxylic acid (5.73 g, 21.8 mmol, 1.0 eq) in DCM (50 mL), was added TEA (12.1 mL, 87.2 mmol, 4.0 eq). The reaction mixture was cooled to 0 C. After 10 min, HATU (9.94 g, 26.2 mmol, 1.2 eq) was added, and the reaction mixture was stirred at 0 C for 1 h and then at room temperature overnight. The mixture was washed subsequently with 0.1 M HCl-solution, 5% NaHC0 ; water and brine. It was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=200: l - 50: 1) to afford the desired product 1 (7.13 g, yield 84.4 %). LCMS: m/z = 389 [M+H]+. | |
73% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | 2-Chloro-3-aminomethylpyrazine HCl (2 g; 11.1 minol), (5)-(-)-l-(carbobenzyloxy)-2- piperidine carboxylic acid (3.2 g; 12.2 minol) and N,N-diisopropylethylamine (7.7 mL; 44.4 minol) were dissolved in dichloromethane (100 mL). N-[(dimethylamino)-lH-l,2,3-triazolo- [4,5-6]pyridin-l -ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) (6.3 g; 16.7 minol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was washed with aqueous sodium bicarbonate solution and water. The organic layer was then dried over sodium sulfate, filtered and evaporated to dryness. The crude material was chromatographed over S1O2 using a gradient of 20 -80% ethyl acetate in heptane to give 4.4 g; 11.3 minol of benzyl (2<S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]piperidine-l- carboxylate (1-1) as a colorless oil (73%). Data: LCMS Rt = 5.85 min; m/z 389.2 (M+H)+; HPLC Rt = 8.30 min; NMR (400 MHz, CDCh, 300 K): delta = 8.35 (IH, d), 8.29 (IH, d), 7.35 (5H, bs), 5.20 (2H, s), 4.95 (IH, s), 4.76 (IH, d), 4.60 (IH, dd), 4.18 (IH, bs), 3.03 (IH, bs), 2.36 (IH, bd), 1.88 - 1.47 (6H, m). |
54.6% | With triethylamine; HATU; In dichloromethane; at 0 - 20℃; | (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate To a solution of (3-chloropyrazin-2-yl)methanamine.HCI (3.60 g, 19.98 mmol, 40% wt) and (S)- 1-N-Cbz-pipecolinic acid (2.63 g, 9.99 mmol) in dichloromethane (40 mL) was added triethylamine (2.78 mL, 19.98 mmol) and the reaction mixture was cooled to 0C. After 15 min stirring at 0C, HATU (4.18 g, 10.99 mmol) was added. The mixture was stirred for 1 hour at 0C and then overnight at room temperature. The mixture was washed with 0.1 M HCI-solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (dichloromethane/methanol = 99/1 to 97/3 v/v% + triethylamine) to give 2.12 g of (S)-benzyl 2-((3-chloropyrazin-2- yl)methylcarbamoyl)piperidine-1-carboxylate (54.6%). |
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | 2-Chloro-3- aminomethylpyrazine.HCl (2 g; 11.1 mmol), <strong>[28697-11-2](S)-(-)-1-(carbobenzyloxy)-2-piperidine carboxylic acid</strong> (3.2 g; 12.2 mmol) and N,N-diisopropylethylamine (7.7 mL; 44.4 mmol) were dissolved in dichloromethane (100 mL). HATU (6.3 g; 16.7 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was washed with aqueous sodium bicarbonate solution and water. The organic layer was then dried over sodium sulfate, filtered and evaporated to dryness. The crude material was chromatographed over SiO2 using a gradient of 20-80% ethyl acetate in heptane to give 4.4 g; 11.3 mmol of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]piperidine- 1-carboxylate as a colorless oil (73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 0.333333h;Microwave irradiation; | (3-Chloropyrazin-2-yl)methanamine hydrochloride (157 mg, 0.873 mmol), 2-chloro-4- methoxyphenylboronic acid (325 mg, 1.75 mmol), potassium carbonate (482 mg, 3.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) in water (1.5 mL) and DME (4.5 mL) was microwave irradiated at 110 C for 30 min. After organic solvent was removed in vacuo, the residue was extracted with EtOAc and washed successively with water and brine. The organic layer was dried over Na2S04and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (MeOH/DCM) to obtain 64 mg of [3-(2-chloro-4-methoxy- phenyl)-pyrazin-2-yl]-methylamine. |
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