Structure of 175358-01-7
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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. : | 175358-01-7 |
Formula : | C6H6ClN3O |
M.W : | 171.58 |
SMILES Code : | O=C(N)C1=NC(Cl)=CC=C1N |
MDL No. : | MFCD09750671 |
InChI Key : | ZGGQDDSXBIALBC-UHFFFAOYSA-N |
Pubchem ID : | 10749704 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 41.75 |
TPSA ? Topological Polar Surface Area: Calculated from |
82.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.34 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.35 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.42 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.39 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.45 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.09 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.02 |
Solubility | 16.4 mg/ml ; 0.0953 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.91 |
Solubility | 21.1 mg/ml ; 0.123 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.87 |
Solubility | 2.33 mg/ml ; 0.0136 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 |
No |
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 |
-7.6 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) |
1.73 |
* 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 |
---|---|---|
80% | at 140℃; for 2h; | Add 3 (2.5g, 14.6mmol) and triethyl orthoformate (100mL, 60mmol) in a 250mL eggplant-shaped bottle, react at 140 for 2h, complete reaction by TLC, cool to room temperature, filter to obtain filter cake, and dry to light yellow Solid 2.1g, yield 80%. |
72% | for 3h;Heating / reflux; | A suspension of e-chloro^-carboxamido-S-amino-pyridine (1.34 mmol, 230 mg) in triethyl orthoformate (10 ml) was refluxed for 3 hours. A white suspension was formed which was cooled down to room temperature. The precipitate was filtered off and dried under vacuum resulting in the pure title compound (174 mg, yield 72 %) which was characterised by its mass spectrum as follows: MS (m/z) : 182, 184([M+H]+, 100). |
42% | With acetic anhydride; for 2h;Reflux; | Acetic anhydride (15.1 mL, 160 mmol) was added to a mixture of 3-amino-6-chloro- pyridine-2-carboxamide (2.50 g, 14.6 mmol) and triethyl orthoformate (15.1 mL, 90.7 mmol). The reaction mixture was refluxed for 2 hours and it was cooled down to 20C which caused the formation of a precipitate. Isopropanol (20 mL) was added and the solid was filtered, washed with isopropanol and dried under vacuum to afford 6-chloropyrido[3,2-d]pyrimidin- 4(3H)-one (1.10 g, 6.06 mmol, 42% yield) as a beige solid. LCMS [M+H+] 182.0. |
at 145℃; for 3h; | a) Method for synthesising P-2a:; Cl theta-chloro^-cyano-S-nitropyridine (9.50 g, 51.76 mmol) is taken up in 150 ml. of 90 % H2SO4 solution. The reaction mixture is stirred for 4 h at 70 0C, cooled and slowly added dropwise to ice water. The precipitate formed is filtered off, washed with water and dried. The aqueous filtrate is extracted 6 x with DCM. The organic phases are combined, dried on Na2SO4, filtered off and concentrated by rotary evaporation. The residue is mixed with the precipitate, dried overnight at 50 0C in the drying cupboard and 6-chloro-3-nitro- pyridine-2-carboxylic acid amide (HPLC-MS: tRet = 0.43 min; MS (M+H)+ = 202) is obtained. theta-chloro-S-nitro-pyridine^-carboxylic acid amide (10.43 g, 51.75 mmol) is taken up in EtOH (250 ml_), combined with ammonium chloride (1.384 g, 25.87 mmol) in water(250 ml.) and heated to 60 0C. At this temperature iron powder (8.67 g, 155.23 mmol) is added batchwise and the mixture is stirred for 1 h at 60 0C. After cooling it is concentrated by rotary evaporation, filtered through silica gel, washed with DCM/MeOH (90/10 to 80/20), the resulting filtrate is evaporated down using the rotary evaporator and 3-amino- theta-chloro-pyridine^-carboxylic acid amide (HPLC-MS: tRet = 0.90 min; MS (M+H)+ = 172) is obtained.S-amino-theta-chloro-pyridine^-carboxylic acid amide (7.45 g, 43.41 mmol) is taken up in triethylorthoformate (150 mL) and stirred for 3 h at 145 0C. After cooling the precipitate formed is filtered off, washed with Et2O, dried and 6-chloro-3/-/-pyrido[3,2-d]pyrimidin-4- one (HPLC-MS: tRet = 0 min; MS (M+H)+ = 182) is obtained.6-chloro-3/-/-pyrido[3,2-d]pyrimidin-4-one (7.16 g, 39.43 mmol) and Lambda/,Lambda/-diethylaniline (9.505 mL, 59.14 mmol) are taken up in toluene (185 mL) and heated to 110 0C. Then POCI3 (3.713 mL, 39.43 mmol) is slowly added dropwise. The reaction mixture is stirred for a further 4 h at 110 0C. After cooling the mixture is diluted with toluene, washed 2 x with water, 2 x with 20 % NaOH solution and 1 x with 1 M HCI solution. The organic phase is dried on MgSO4, filtered off, evaporated down and P-2a is obtained (HPLC-MS: tRet = 1.14 min).Method of synthesis from: J. Med. Chem. 1996, 39, 1823-1835. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iron; ammonium chloride; In ethanol; water; at 60℃; for 1.0h; | Pyridine Z.5 (2.00 g, 1 0.0 mmol) and iron filings (2.77 g, 49.6 mol) are taken up in EtOH/H20 (100 mL, 1 :1 ), combined with NH4CI (265 mg, 4.91 mmol) and heated to 60C for 1 h. The solvent is removed, the residue is taken up in DCM/MeOH (50 mL, 9:1 ), filtered through Celite, the solvent is eliminated again and pyridine Z.6 (1 .57 g, 92 %) is obtained. |
92% | With iron; ammonium chloride; In ethanol; water; at 60℃; for 1.0h; | Method of Synthesising the Azaquinazolines D*.2 and D.2Pyridine ED.4 (10.0 g, 54.5 mmol) is taken up in H2SO4 (150 mL, 90%) and heated to 70 C. for 3.5 h. Then the reaction mixture is cooled to 20 C., added dropwise to ice water, the precipitate is filtered off, washed with H2O, dried and pyridine Z.5 (10.5 g, 95%) is obtained.Pyridine Z.5 (2.00 g, 10.0 mmol) and iron filings (2.77 g, 49.6 mol) are taken up in EtOH/H2O (100 mL, 1:1), combined with NH4Cl (265 mg, 4.91 mmol) and heated to 60 C. for 1 h. The solvent is removed, the residue is taken up in DCM/MeOH (50 mL, 9:1), filtered through Celite, the solvent is eliminated again and pyridine Z.6 (1.57 g, 92%) is obtained.Pyridine Z.6 (500 mg, 2.91 mmol) is taken up in triethylorthoformate (10 mL) and heated to 145 C. for 18 h. Then the reaction mixture is cooled to 20 C., the precipitate is filtered off, washed with Et2O (10 mL), dried and azaquinazolone Z.7 (433 mg, 82%) is obtained.Azaquinazolone Z.7 (200 mg, 1.10 mmol) is placed in toluene (5.0 mL), combined with N,N-diethylaniline (0.27 mL) and POCl3 (0.88 mL) and heated to 110 C. for 4 h. The reaction mixture is cooled to 20 C., diluted with toluene (5 mL) and H2O (5 mL), washed with NaOH (3×10 mL, 20%) and HCl (2×10 mL, 1 M), dried on Na2SO4, filtered, freed from the solvent and azaquinazoline D*.2 (165 mg, 75%) is obtained.Azaquinazoline D*.2 (1.15 g, 5.75 mmol) is placed in DCM (5.0 mL), cooled to 0 C., combined with methylamine (3.5 mL, 7.19 mmol, 2 M in THF) and DIPEA (3.0 mL), the reaction mixture is heated to 20 C. and stirred for 1 h at 20 C. The solvent is removed, the residue is taken up in H2O, the precipitate is filtered off, washed with H2O and azaquinazoline D.2 (640 mg, 57%; HPLC-MS: MS (M+H)+=195; tRet.=1.85 min; method 1_BAS). |
89% | With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 3.0h; | 6-Chloro-3-nitropicolinamide, 4.80 g (23.8 mmol), and palladium carbon (10%), 0.67 g (6.3 mmol), were added into 60 ml_ of ethyl acetate. The resulting mixture was stirred under hydrogen atmosphere (2 atm) for 3 hours at room temperature. Then palladium on carbon was filtered out and washed with ethyl acetate. The solvent was removed in vacuo to give 3.79 g (89%) of the product as a yellow solid. MS (ESIpos): m/z = 172 (M+H)+; LC-MS (Method 4, Acetonitrile-Water-0.1 % FA-10%B): Rt = 0.59 min. |
With iron; ammonium chloride; In ethanol; water; at 60℃; for 1.0h; | a) Method for synthesising P-2a:; Cl theta-chloro^-cyano-S-nitropyridine (9.50 g, 51.76 mmol) is taken up in 150 ml. of 90 % H2SO4 solution. The reaction mixture is stirred for 4 h at 70 0C, cooled and slowly added dropwise to ice water. The precipitate formed is filtered off, washed with water and dried. The aqueous filtrate is extracted 6 x with DCM. The organic phases are combined, dried on Na2SO4, filtered off and concentrated by rotary evaporation. The residue is mixed with the precipitate, dried overnight at 50 0C in the drying cupboard and 6-chloro-3-nitro- pyridine-2-carboxylic acid amide (HPLC-MS: tRet = 0.43 min; MS (M+H)+ = 202) is obtained. theta-chloro-S-nitro-pyridine^-carboxylic acid amide (10.43 g, 51.75 mmol) is taken up in EtOH (250 ml_), combined with ammonium chloride (1.384 g, 25.87 mmol) in water(250 ml.) and heated to 60 0C. At this temperature iron powder (8.67 g, 155.23 mmol) is added batchwise and the mixture is stirred for 1 h at 60 0C. After cooling it is concentrated by rotary evaporation, filtered through silica gel, washed with DCM/MeOH (90/10 to 80/20), the resulting filtrate is evaporated down using the rotary evaporator and 3-amino- theta-chloro-pyridine^-carboxylic acid amide (HPLC-MS: tRet = 0.90 min; MS (M+H)+ = 172) is obtained.S-amino-theta-chloro-pyridine^-carboxylic acid amide (7.45 g, 43.41 mmol) is taken up in triethylorthoformate (150 mL) and stirred for 3 h at 145 0C. After cooling the precipitate formed is filtered off, washed with Et2O, dried and 6-chloro-3/-/-pyrido[3,2-d]pyrimidin-4- one (HPLC-MS: tRet = 0 min; MS (M+H)+ = 182) is obtained.6-chloro-3/-/-pyrido[3,2-d]pyrimidin-4-one (7.16 g, 39.43 mmol) and Lambda/,Lambda/-diethylaniline (9.505 mL, 59.14 mmol) are taken up in toluene (185 mL) and heated to 110 0C. Then POCI3 (3.713 mL, 39.43 mmol) is slowly added dropwise. The reaction mixture is stirred for a further 4 h at 110 0C. After cooling the mixture is diluted with toluene, washed 2 x with water, 2 x with 20 % NaOH solution and 1 x with 1 M HCI solution. The organic phase is dried on MgSO4, filtered off, evaporated down and P-2a is obtained (HPLC-MS: tRet = 1.14 min).Method of synthesis from: J. Med. Chem. 1996, 39, 1823-1835. |