Structure of 680210-85-9
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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. : | 680210-85-9 |
Formula : | C10H5ClN2O |
M.W : | 204.61 |
SMILES Code : | N#CC1=C(Cl)C2=C(NC1=O)C=CC=C2 |
MDL No. : | MFCD01570117 |
InChI Key : | JWBMUCZTOBYSEM-UHFFFAOYSA-N |
Pubchem ID : | 2777510 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 54.29 |
TPSA ? Topological Polar Surface Area: Calculated from |
56.65 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.53 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.61 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.05 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.55 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.98 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.65 |
Solubility | 0.457 mg/ml ; 0.00223 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.41 |
Solubility | 0.793 mg/ml ; 0.00388 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.32 |
Solubility | 0.00988 mg/ml ; 0.0000483 mol/l |
Class? Solubility class: Log S scale |
Moderately 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 |
-6.41 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) |
1.76 |
* 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 |
---|---|---|
88% | In toluene; at 110℃; | PIPERAZINE-1-YL-THIOPHEN-2-YL-METHANONE (8.0 g, 41 mmol) was added to a solution of Compound 115 (4.1 g, 20 mmol) in toluene (50 mL) and heated overnight at 110 C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0-2% methanol in dichloromethane gradient to yield 6.4 g (88%) of white solids. M. P. 264 C. LH NMR (DMSO-d6): d 3.7 (m, 4H), 3.9 (m, 4H), 7.16 (t, J= 4.8 Hz, 1H), 7.23 (t, J= 5.9 Hz, 1H), 7.31 (d, J= 8.6 Hz, 1H), 7.49 (d, J= 4.0 Hz, 1H), 7.61 (t, J= 8.3 Hz, 1H), 7.8 (m, 2H), 11.90 (b, 1H) ; EIMS: 364 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With ammonium acetate; acetic acid; at 140℃; for 4h; | Ammonium acetate (2.1 g, 27 mmol) was added to a suspension of Compound 114 (6.0 g, 27 mmol) in glacial acetic acid and heated at 140 C for 4 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried under vacuum to yield 5.2 g (94%) of white solids. M. P. 302C. 1H NMR (DMSO-DS) : d 1H-NMR (DMSO-d6): 7. 4 (m, 2H), 7.79 (T, J= 7.6 Hz, 1H), 7.96 (d, J= 8. 0 Hz, 1H), ; EIMS : 205 (M+H). |
77% | With ammonium acetate; acetic acid; at 140℃; for 4h; | 2,4-dichloroquinoline-3-carbonitrile (Example 72a) (0.95 g, 4.26 mmol) and ammonium acetate (0.36 g, 4.67 mmol) were heated in acetic acid (20 mL) at 140 C. for 4 hours, then cooled to room temperature. The reaction was poured into ice water (400 mL), and the resultant precipitate was collected by filtration to give 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.668 g, 77%) as a light yellow solid. M.p.: >250 C. 1H NMR (400 MHz, DMSO-d6) delta 7.42 (m, 2H), 7.79 (m, 1H), 7.96 (d, J=8.4 Hz, 1H), 12.72 (s, 1H). MS 205 (MH-). |
With water; trifluoroacetic acid; at 100℃; for 1h; | 4-chloro-2-oxo-L2-dihvdroquinoline-3-carbonitrile (1-5) In a round-bottomed flask, 2,4-dichloroquinoline-3-carbonitrile (1-4) (15g, 67.2mmol), was dissolved in 40 ml of a 4: 1 mixture of TFA and H20. The reaction mixture was heated to 100 C for 1 hour, then allowed to cool and poured into methanol. The precipitate was filtered off and dried to give 4-chloro-2-oxo-l,2-dihydroquinoline-3-carbonitrile (1-4) HRMS (M+H)+: observed = 205.1, calculated = 205.6 |
With trifluoroacetic acid; In water; at 100℃; for 1h; | In a round-bottomed flask, 2,4-dichloroquinoline-3-carbonitrile (1-4) (15g, 67.2mmol), was dissolved in 40 ml of a 4: 1 mixture of TFA and H20. The reaction mixture was heated to 100 C for 1 hour, then allowed to cool and poured into methanol. The precipitate was filtered off and dried to give 4-chloro-2-oxo-l,2-dihydroquinoline-3-carbonitrile (1-4) HRMS (M+H)+: observed = 205.1, calculated = 205.6 | |
With trifluoroacetic acid; In water; at 100℃; for 1h; | In a round-bottomed flask, 2,4-dichloroquinoline-3 -carbonitrile (1-4) (1 5g,67.2mmol), was dissolved in 40 ml of a 4:1 mixture of TFA and H20. The reaction mixture was heated to 100C for 1 hour, then allowed to cool and poured into methanol. The precipitate was filtered off and dried to give 4-chloro-2-oxo- 1 ,2-dihydroquinoline-3 -carbonitrile (1-4) HRMS(M+H): observed = 205.1, calculated = 205.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In the same manner as shown in Reference Example 24, the target compound was obtained. 1H-NMR (DMSO-d6, 300 MHz): delta 7.37-7.43 (2H, m), 7.75-7.81 (1H, m), 7.94-7.97 (1H, m), 12.70 (1H, br s). LC/MS (ESI): m/z 205.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | <strong>[680210-85-9]4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile</strong> (example 72) (0.66 g, 3.23 mmol) was suspended in DMF (7 mL), and 4-methoxybenzylamine (0.94 mL, 7.26 mmol) was added. The reaction was heated at 100 C. for 1 hour and the DMF was removed under vacuum. The residue was dissolved in TFA (6 mL) and stirred at room temperature for 30 minutes and dichloromethane (10 mL) was added. The solid product that formed was collected, suspended in water and the solution stirred overnight. The solid was collected by filtration to give 4-amino-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.150 g, 25%) as a white solid. M.p.: >250 C. 1H NMR (400 MHz, DMSO-d6) delta 7.19 (m, 2H), 7.57 (m, 1H), 7.88 (bs, 2H), 8.12 (d, J=7.6 Hz, 1H), 11.23 (s, 1H). MS 186 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(tri-t-butylphosphine)palladium(0); caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.166667h;Microwave irradiation; Inert atmosphere; Sealed tube; | 4-phenyl-2-oxo-L2-dihydroquinoline-3-carbonitrile (1-7) To a microwave vial, 4-chloro-2-oxo-l,2-dihydroquinoline-3-carbonitrile (1-5, lg, 4.89 mmol) was added along with phenylboronic acid 1-6 (969 mg, 9.77 mmol), cesium carbonate (1.263g, 9.77 mmol), and DMF (3 mL). The reaction was degassed, then bis(tri-t- butylphosphine)palladium(O) (51 mg, 0.1 mmol) was added. The sealed reaction vessel was heated under microwave irradiation for 10 min at 100 C. The reaction mixture was partitioned between AcOEt (3x75 ml) and saturated aqueous NaHC03 (80 ml). The combined organic layers were dried over MgS04 and concentrated. The yellow solid was then redissolved in AcOEt and recrystalized to give 4-phenyl-2-oxo-l,2-dihydroquinoline-3-carbonitrile (1-7). MR (500 MHz, DMSO-d6): delta 12.6 (s, 1 H); 7.71 (m, 1 H); 7.62 (m, 3 H); 7.53 (m, 2 H); 7.45 (m, 1 H); 7.21 (m, 2 H). MS (M+H)+: observed = 247.2, calculated = 247.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a microwave flask charged with DMF (0.3 ml), cyclohexanol (50 mg, 0.499 mmol) was added, followed by NaH (20 mg 60% dispersion in mineral oil, 0.499 mmol), portionwise. The reaction mixture was stirred at r.t. for 1 hour then 4-chloro-2-oxo-l,2- dihydroquinoline-3-carbonitrile (1-4, 51. lmg, 0.250 mmol) was added. The reaction was heated to 110 C under microwave irradiation for 10 min, cooled, the solvent removed and the crude residue was purified via reverse phase to give 4-(cyclohexyloxy)-2-oxo-l,2-dihydroquinoline-3-carbonitrile (1-7). NMR (500 MHz, DMSO-d6): delta 12.1 (s, 1 H); 7.91 (m, 1 H); 7.68 (m, 1 H); 7.35-7.23 (m, 2 H); 5.22 (m, 1 H); 2.09 (m, 2 H); 1.80-1.69 (m, 4 H); 1.59-1.25 (m, 4 H). HRMS (M+H)+: observed = 268.31, calculated = 268.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 0.5h; | 4-Chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1-5) (20g, 98 mmol), 1-pyrrolidine-3-yl-1H-pyrazole hydrochloride (23.8 g, 137 mmol), DIPEA (68.3 mL, 391 mmol), andDMF (244 mL) were heated to 100 C for thirty minutes. The reaction was cooled and partitionedbetween water and EtOAc, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were concentrated, and the residue slurried in water to result in a brown solid which was collected by filtration. The mother liquor was aged overnight and the resulting additionalbrown material was collected by filtration. The combined solids were purified by SCF method(55% C02, 45% MeOH, IA column with 0.1% DEA additive), and the second peak (6.55 mm.)collected to give the single enantiomer (R)-4-(3 -[ 1H-pyrazol- 1 -yl]pyrrolidin- 1 -yl)-2-oxo- 1,2-dihydroquinoline-3-carbonitrile (1-7) as a beige solid (9.1 g, 3 1%). ?HNIVIR (500 MHz, CD3OD):8.09 (m, 1 H); 7.78 (m, 1 H); 7.5 1-7.59 (m, 2 H); 7.25 (m, 1 H); 7.19 (m, 1 H); 6.33 (m, 1 H);5.18 (m, 1 H); 4.58 (m, 1 H); 4.44 (m, 1 H); 4.40 (m, 1 H); 4.29 (m, 1 H); 2.53 (m, 2 H). MS(M+H): observed = 306.08, calculated = 306.334 |