Structure of 78881-21-7
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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. : | 78881-21-7 |
| Formula : | C8H8N2 |
| M.W : | 132.16 |
| SMILES Code : | NC1=C(C=C(C#N)C=C1)C |
| English Name : | 4-Amino-3-methylbenzonitrile |
| MDL No. : | MFCD02093969 |
| InChI Key : | MBZDCUMFFPWLTJ-UHFFFAOYSA-N |
| Pubchem ID : | 7010316 |
| Num. heavy atoms | 10 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.12 |
| Num. rotatable bonds | 0 |
| Num. H-bond acceptors | 1.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 40.53 |
| TPSA ? Topological Polar Surface Area: Calculated from |
49.81 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.48 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.98 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.46 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.12 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.54 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.32 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.72 |
| Solubility | 2.51 mg/ml ; 0.019 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.61 |
| Solubility | 3.21 mg/ml ; 0.0243 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.48 |
| Solubility | 0.442 mg/ml ; 0.00334 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) |
Yes |
| 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 |
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) |
1.22 |
* 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 |
|---|---|---|
| 96% | With ethanol; tin(ll) chloride for 2h; Heating; | |
| 93% | With 10% Pd/C; hydrogen In tetrahydrofuran; methanol at 20℃; | To a stirring 100 mL solution of THF at room temperature, added 9.89 g (61 mmol, 1 eq) of the benzonitrile. Then added 1 g palladium over 10% carbon. Then added 25 mL of methanol. The system was then put under 50 psi of pressure in a hydrogenator. After no more hydrogen consumption was observed, the reaction was stopped and filtered over celite. Performed column chromatography using 1:1 hexane:dichloromethane as the mobile phase. Obtained 7.5 g of a beige powder. Yield was 93%. 1H-NMR (DMSO): δ 2.27 (3H, s), 6.06 (2H, s), 6.41 (1H, d), 6.46 (1H, s), 7.30 (1H, d). |
| 92% | With hydrogenchloride; tin(ll) chloride In water; acetic acid for 3h; | A1a Synthesis of 4-cyano-2-methylaniline 4-Cyano-2-methylaniline was synthesized as previously described (J. Med. Chem. (1991), 34, 3295): To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L) was added dropwise a solution of SnCl2 (9.6 g, 49.38 mmol) in conc. HCl (20 mL). After stirring for 3 h, the mixture was added carefully to a saturated NH4OH solution (120 mL) at 0° C. The resulting mixture was extracted with EtOAc (4×30 mL). The combined organic layers were sequentially washed with H2O (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc/hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%): TLC (30% EtOAc in hexane) Rf0.23. This material was used without further purification |
| 92% | With iron; acetic acid at 20℃; for 14.1667h; | 4-Amino-3-methyl-benzonitrile: To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexane) to yield the title compound (15.3 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+m/z 133 (t=0.93 min). |
| 92% | With iron; acetic acid at 20℃; for 14h; | 4-Amino-3-methyl-benzonitrile: To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexane) to yield the title compound (15.3 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 133 (t=0.93 min). |
| 92.2% | With ammonium chloride; zinc In methanol at 15℃; for 16h; | 15.1 Step 1: 4-Amino-3-methyl-benzonitrile _ To a solution of 3-methyl-4-nitro-benzonitrile (3 g, 18.50 mmol, 1 eq) in MeOH (30 mL) was added Zn (12.10 g, 185.00 mmol, 10 eq) and NH4Cl (9.90 g, 185.00 mmol, 10 eq). The mixture was stirred at 15° C. for 16 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield crude 4-amino-3-methyl-benzonitrile (2.3 g, 17.05 mmol, 92.2% yield, 98.0% purity) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (dd, J=2.9, 3.9 Hz, 2H), 6.68-6.61 (m, 1H), 4.24-3.90 (m, 2H), 2.16 (s, 3H); ES-LCMS m/z 155.1 [M+Na]+. |
| 74% | With iron; acetic acid | |
| 61% | With hydrogenchloride; tin(ll) chloride In acetic acid for 3h; | |
| With hydrogenchloride; tin(ll) chloride | ||
| With stannous chloride; sodium hydrogencarbonate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol | 16.A A. A. 4-Amino-3-methyl benzonitrile To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is heated at reflux. After 2 hours, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid. 1 H NMR (CDCl3, 300 MHz) δ 7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M]+ =132. | |
| With stannous chloride; sodium hydrogencarbonate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol | 68.A 4-Amino-3-{3-(S)-[(7-methoxy-naphthalene-2-sulfonyl)-pyridine-2-ylmethyl-amino]-2-oxo-pyrrolidin-1-ylmethyl}-benzamidine trifluoroacetate. A. 4-Amino-3-methylbenzonitrile. To a solution of 3-methyl-4-nitrobenzonitrile (2 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is refluxed. After 2 hours, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid. 1 H NMR (CDCl3, 300 MHz) δ7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M]+ =132. | |
| With stannous chloride; sodium hydrogencarbonate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol | 16.A A. A. 4-Amino-3-methyl benzonitrile To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is heated at reflux. After 2 h, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid. 1 H NMR (CDCl3, 300 MHz) δ7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M]+ =132. | |
| 12 g (61%) | With ammonium hydroxide In hydrogenchloride; acetic acid | 1.C (4-cyano-2-methylaniline) C. To a stirred, 25° C. solution of 3-methyl-4-nitrobenzonitrile (24 g, 0.148 mol) in acetic acid (250 mL) under nitrogen was added dropwise a solution of SnCl2.2H2 O (133.57 g., 0.592 mol) in concentrated HCl (250 mL). After stirring for 3 hours, the reaction mixture was added carefully to excess cold ammonium hydroxide. The reaction mixture was extracted several times with ethyl ether. The organic extracts were then combined, dried (Na2 SO4) and evaporated under reduced pressure to afford 12 g (61%) of the title compound, 4-cyano-2-methylaniline, as a white solid; m.p. 64°-66° C. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: dibenzoyl peroxide; sulfuryl dichloride / tetrachloromethane / 3 h / 100 °C 3.1: N,N-dimethyl-formamide / 7 h / 140 - 155 °C 4.1: borane-THF / tetrahydrofuran / 20 °C / Cooling with ice; Inert atmosphere 4.2: 0.17 h / 20 °C | ||
| Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: sulfuryl dichloride / dibenzoyl peroxide / tetrachloromethane / 3 h / 100 °C 3.1: toluene / 3 h / 110 °C 4.1: N,N-dimethyl-formamide / 2 h / 155 °C 5.1: borane-THF / tetrahydrofuran / 20 °C / Inert atmosphere; Cooling with ice-water 5.2: 0.17 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 85% 2: 14% | Stage #1: 3-iodophthalic anhydride; 2-methyl-1-methylthio-2-propylamine With triethylamine In dichloromethane at 20℃; Stage #2: With methanesulfonyl chloride; triethylamine In dichloromethane at -10℃; Stage #3: 4-amino-3-methylbenzonitrile In dichloromethane at -10 - 20℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With phosphorus trichloride In chlorobenzene at 150℃; for 1h; Microwave irradiation; | General synthetic procedure for 8-Hydroxyquinoline carboxamides General procedure: Phosphorus trichloride (1.0 mmol) is added to a stirred solution of 8-hydroxyquinoline-7-carboxylic acid (1.0mmol) and aniline (1.00mmol) in chlorobenzene (3 mL). The resulting solution is heated at 150 oC for 1 hour via microwave irradiation. The cooled solution is evaporated to dryness sunder reduced pressure. The residue was suspended between EtOAc, 1M NaOH and brine solution (25 mL), filtered and triturated in a warm mixture of EtOH and MeOH (40 mL). The collected mixture was filtered and dried under reduced pressure to give the desired product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: boron trichloride / toluene / 0.5 h / 0 - 5 °C / Cooling with ice 1.2: 20.5 h / 0 - 80 °C 2.1: tetrahydrofuran / 4 h / 20 - 25 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1.1: boron trichloride / toluene / 0.5 h / 0 - 5 °C 1.2: 20.5 h / 0 - 80 °C 1.3: 1 h / 0 - 80 °C / Inert atmosphere 2.1: tetrahydrofuran / 4 h / 20 - 25 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: aluminum (III) chloride; boron trichloride / toluene; dichloromethane / 4 h / 80 °C 2: tetrahydrofuran; water / 20 °C |
| Multi-step reaction with 2 steps 1: aluminum (III) chloride; boron trichloride / toluene; dichloromethane / 4 h / 80 °C 2: tetrahydrofuran; water / 20 °C |
