Structure of 1201924-31-3
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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. : | 1201924-31-3 |
Formula : | C7H5ClN2 |
M.W : | 152.58 |
SMILES Code : | N#CC1=NC(Cl)=CC=C1C |
MDL No. : | MFCD16658734 |
InChI Key : | GRLXSZKHRDKVTE-UHFFFAOYSA-N |
Pubchem ID : | 46856278 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 38.93 |
TPSA ? Topological Polar Surface Area: Calculated from |
36.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.76 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.92 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.73 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.4 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.81 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.63 |
Solubility | 0.354 mg/ml ; 0.00232 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.64 |
Solubility | 0.353 mg/ml ; 0.00231 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.1 |
Solubility | 0.122 mg/ml ; 0.0008 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) |
Yes |
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 |
-5.65 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 |
1.0 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) |
1.92 |
* 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 |
---|---|---|
Step 2. 6-Chloro-3-methylpyridine-2-carbonitrile3-Methylpyridme-2-carbordtrile 1 -oxide (8.42 g, 62.8 mmol) was stirred in refluxing POCl3 (60 mL, 646 mmol) for 6 hours. The mixture was cooled to room temperature and slowly poured into ice- water. The resulting beige precipitate was collected by filtration to give the title compound.1H NMR (600 MHz, CDCl3): delta 7.62 (d, J- 8.4 Hz, 1 H), 7.43 (d, J- 8.4 Hz, 1 H), 2.53 (s, 3 H). | ||
With trichlorophosphate; In toluene; at 90.0℃; for 1.5h; | To a round bottom flask is added 3-methyl-l-oxo-pyridine-2- carbonitrile (16.2 g, 120.77 mmoles), toluene (8 mL), and phosphoryl chloride (16.83 mL; 181.2 mmoles). The mixture is stirred at 90 C for 90 minutes, cooled to RT, and added dropwise to aqueous 2M KH2PO4 (483 mL; 966 mmoles). The mixture is stirred 30 minutes, and the layers are separated. The organic layer is dried over MgS04, filtered, and concentrated to 6-chloro-3-methyl-pyridine-2-carbonitril: Mass spectrum (m/z): 153.0 (M+H)+. Phenylboronic acid (17.94 g, 144.9 mmoles), toluene (130 mL), sodium carbonate (190.2 g, 362.31 mmoles), bis(triphenylphosphine)palladium(II) chloride (856 mg; 1.21 mmoles) are added to this crude material. The mixture is stirred at 80C for 1 hour and cooled to RT. The layers are separated, and the organic layer is dried over MgS04, filtered, and concentrated. The material was purified by silica gel chromatography (400 g ISCO cartridge) using methylene chloride in hexanes from 20 to 100% to afford 3-methyl-6-phenyl-pyridine-2-carbonitrile (6.7 g, 28.6%). Mass spectrum (m/z): 195.1 (M+H)+. | |
With trichlorophosphate; for 1h;Reflux; | A mixture of the product from Step 1 (1.2 g, 8.95 mmol) in POCl3 (29.7 g, 194 mmol) was stirred at reflux for 1 h. The mixture was cooled to RT, poured into 50 mL of water, and basified with saturated, aqueous NaHCC to pH 7-8, and extracted with EtOAc (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated in vacuo to give the title compound as a solid, which was used in the next step without further purification. LRMS m/z (M+H) 153.1 found, 153.0 required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3. 6-Chloro-3 -methylpyridine-2-carboxylic acid6-Chloro-3-methylrhoyridine-2-carbonitrile (2.95 g, 19.3 mmol) and Potassium hydroxide (3.25 g, 58 mmol) were stirred in refluxing water (60 mL) for 2 hours. The mixture was cooled to room temperature, 30 mL of 2 N HCl was added, followed by the addition of water. The resulting mixture was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a white solid.1H NMR (600 MHz, DMSO): delta 13.45 (br s, 1 H), 7.81 (d, J= 8.4 Hz5 1 H), 7.55 (d, J- 8.4 Hz, 1 H), 2.39 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.7 g | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In toluene; at 80.0℃; for 1h; | To a round bottom flask is added 3-methyl-l-oxo-pyridine-2- carbonitrile (16.2 g, 120.77 mmoles), toluene (8 mL), and phosphoryl chloride (16.83 mL; 181.2 mmoles). The mixture is stirred at 90 C for 90 minutes, cooled to RT, and added dropwise to aqueous 2M KH2PO4 (483 mL; 966 mmoles). The mixture is stirred 30 minutes, and the layers are separated. The organic layer is dried over MgS04, filtered, and concentrated to 6-chloro-3-methyl-pyridine-2-carbonitril: Mass spectrum (m/z): 153.0 (M+H)+. Phenylboronic acid (17.94 g, 144.9 mmoles), toluene (130 mL), sodium carbonate (190.2 g, 362.31 mmoles), bis(triphenylphosphine)palladium(II) chloride (856 mg; 1.21 mmoles) are added to this crude material. The mixture is stirred at 80C for 1 hour and cooled to RT. The layers are separated, and the organic layer is dried over MgS04, filtered, and concentrated. The material was purified by silica gel chromatography (400 g ISCO cartridge) using methylene chloride in hexanes from 20 to 100% to afford 3-methyl-6-phenyl-pyridine-2-carbonitrile (6.7 g, 28.6%). Mass spectrum (m/z): 195.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90.0℃;Inert atmosphere; | To a stirred mixture of the product from Step 2 (200 mg, 1.31 mmol), Pd(Ph3P)4 (76 mg, 0.066 mmol), and Na2C03 (278 mg, 2.62 mmol) in toluene (4 mL), EtOH (2 mL), and water (1 mL) was added potassium vinyltrifluoroborate (263 mg, 1.97 mmol) under N2. The resulting mixture was stirred at 90C overnight. The mixture was cooled to RT, and then the organic layer was separated. The organic phase was washed with water (5 mL x 2), dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 145.1 found, 145.1 required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100.0℃; | A mixture of <strong>[1201924-31-3]6-chloro-3-methyl-pyridine-2-carbonitrile</strong> (914 mg, 5.99 mmol), 2,2- dimethylpiperazine (1000 ilL, 7.30 mmol) and cesium carbonate (2.27 g, 6.97 mmol) in NMP (12 mL) is heated at 100C overnight. The reaction is cooled down to room temperature and water (120 mL) is added. The mixture is extracted with Et20 (3 x 50 mL). The combined organic phases are washed with water (60 mL) and brine (60 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude material isused without further purification in the next step (1.082g, 69%). ESI-MS m/z calc. 230.15315, found 230.68 (M+1)+; Retention time: 1.03 minutes using Method L. |
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