Structure of 34403-48-0
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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. : | 34403-48-0 |
| Formula : | C9H10N2 |
| M.W : | 146.19 |
| SMILES Code : | CNCC1=CC=C(C=C1)C#N |
| English Name : | 4-((Methylamino)methyl)benzonitrile |
| MDL No. : | MFCD09738490 |
| InChI Key : | DWXAJFNXJVIBDP-UHFFFAOYSA-N |
| Pubchem ID : | 10606883 |
| Num. heavy atoms | 11 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.22 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 43.73 |
| TPSA ? Topological Polar Surface Area: Calculated from |
35.82 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.93 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.95 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.13 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.17 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.81 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.4 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.62 |
| Solubility | 3.54 mg/ml ; 0.0242 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.29 |
| Solubility | 7.51 mg/ml ; 0.0514 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.31 |
| Solubility | 0.0724 mg/ml ; 0.000495 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 |
-6.52 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) |
1.18 |
* 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 |
|---|---|---|
| 81% | Stage #1: 4-cyanobenzyl bromide; methylamine In ethanol; water for 2h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 193 Methylamine (350 ml of a 40% aqueous solution, 4.06 mol) was added to a solution of 4-(bromomethyl)benzonitrile (51.3 g, 262 mmol) in EtOH (500 ml). After 2 h, the solvent was removed in vacuo and CH2Cl2 (500 ml) and aqueous saturated NaHCO3 solution (400 ml) were added. The organic phase was separated off and extracted with aqueous saturated NaCl solution (250 ml), over Na2SO4, and the solvent was removed after filtration in vacuo. The residue was taken up in 1 M HCl in Et2O (300 ml) and stirred for 30 min., then filtered off and washed with Et2O. The residue was taken up in H2O (500 ml), rendered basic with aqueous 6 M NaOH and extracted with CH2Cl2 (500 ml). The organic phase was dried over Na2SO4 and filtered off, and the solvent was removed in vacuo. Yield: 31.17 g, 81% |
| 37% | In ethanol; water for 20h; | INTERMEDIATE 64-[(Methylamino)methyl]benzonitrileMethylamine (40% wt in H20, 25 mL, 322 mmol) was added to a solution of 4-(bromomethyl)benzonitrile (4.00 g, 20.4 mmol) in EtOH (40 mL) and the reaction mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography to give the title compound (1 .10 g, 37%) as a yellow oil. LCMS: ES+ 147.1 [MH]+. |
| In methanol for 65h; Heating; |
| In ethanol for 6h; Heating; | ||
| In ethanol; water | ||
| In tetrahydrofuran at 20℃; | I.1 1.1 ) Preparation of 4-(methylaminomethyl)benzonitrile (0517) To a solution of 4-(bromomethyl)benzonitrile (49 g, 1 eq.) in tetrahydrofuran (500 ml.) methylamine (194 g of a 40% solution by weight, 10 eq.) was added. The mixture was stirred overnight at room temperature. After removing the solvent under reduced pressure, an aqueous solution of sodium chloride was added and the aqueous mixture was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate and freed from solvent. The title compound (35.6 g) was used directly without further purification. | |
| 35.6 g | In tetrahydrofuran at 20℃; | I.1 1.1) Preparation of 4-(methylaminomethyl)benzonitrile To a solution of 4-(bromomethyl)benzonitrile (49 g, 1 eq.) in tetrahydrofurane (500 mL) methylamine (194 g of a 40% solution by weight, 10 eq. ) was added. The mixture was stirred overnight at room temperature. After removing the solvent under reduced pressure, an aqueous solution of sodium chloride was added and the aqueous mixture was extracted with ethylacetate. The combined organic layer was dried with magnesium sulfate and freed from solvent. The title compound (35.6 g) was used directly without further purification. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With sodium tetrahydroborate; boric acid for 0.333333h; | |
| 97% | With sodium tetrahydroborate; benzoic acid at 25℃; for 0.333333h; | |
| 11.4 g (78%) | With sodium hydroxide; sodium tetrahydroborate In ethanol | 37.ii (ii) (ii) Methyl-4-cyanobenzylamine NaBH4 (4.54 g; 0.42 mol) was added in portions to an ice-cold solution of methyl-4-cyanobenzylideneimine (14.4 g; 0.1 mol; from step (i) above) in EtOH. The solution was stirred at RT overnight and the resultant solution was quenched with HCl (2M; aq.), washed with ether (2*), made alkaline with NaOH (2M; aq.) to pH 10, and extracted with EtOAc (3*). The organic solution was washed with water and brine, dried (Na2SO4), and concentrated. Yield 11.4 g (78%). 1H-NMR (300 MHz; CDCl3): δ7.92 (d, 2H); 7.76 (d, 2H); 4.82 (s+b, 5H); 4.40 (s, 2H) |
| With sodium tetrahydroborate In methanol at 5 - 20℃; | ||
| 1.88 g | With sodium tetrahydroborate In methanol at 20℃; for 4h; Inert atmosphere; | |
| With sodium tetrahydroborate In methanol at 0 - 20℃; for 2h; Inert atmosphere; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With dmap In dichloromethane at 20℃; for 48h; | (4-Cyano-benzyl)-methyl-carbamic acid tert-butyl ester (4-Cyano-benzyl)-methyl-carbamic acid tert-butyl ester To 4-[(methylamine)methyl]benzonitrile (1 g, 6.8 mmol) in CH2Cl2 (50 mL) was added DMAP (0.93 g, 7.6 mmol), di-tert-butyl dicarbonate (1.7 g, 7.6 mmol) and the reaction stirred for 48 h at RT. The reaction mixture was washed with saturated, aqueous NaHCO3 and brine. The organic phase was separated and concentrated in vacuo. The crude residue was purified on silica gel chromatography eluting with isohexane, and increasing the polarity to 20% EtOAc/isohexane to afford (4-cyano-benzyl)-methyl-carbamic acid tert-butyl ester as a colourless oil (1.48 g, 89%). AnalpH2_MeOH-4 min: Rt 2.75 min; m/z 247 [M+1]+. |
| 82% | With dmap In dichloromethane at 20℃; for 2h; | CXIV A solution of 1.94 g (13 mM) of [(4-cyanophenyl)methyl]methanamine is prepared in 100 ml of dichloromethane and 1.78 g (14.6 mM) of 4-dimethylaminopyridine, and then 3.19 g (14.6 mM) of di-t-butyl dicarbonate, are added. The reaction mixture is agitated at ambient temperature for 2 hours. The organic phase is washed with water and then with a solution of citric acid, and then with water, and then dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel in eluting with a mixture of toluene/isopropanol (9/1, v/v). 2.91 g of the desired product are thus obtained as a colourless oil (yield=82%). 1H NMR (250 MHz, DMSO) δ: 7.82 (d, 2H); 7.39 (d, 2H); 4.45 (s, 2H); 2.79 (s, 3H); 1.38 (s, 9H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 87% | With triethylamine In dichloromethane at 0 - 20℃; for 20h; | I A mixture of 7 g (47.9 mM) of [(4-cyanophenyl)methyl]methanamine is prepared in 60 ml of DCM and 5.8 g (57.5 mM) of triethylamine are added. The mixture is cooled to 0° C. and a solution of 9.8 g (57.5 mM) of benzyl chloroformate in 20 ml of DCM is added dropwise. The mixture is then agitated for 20 hours at ambient temperature and then washed with a solution of 0.1 N hydrochloric acid, and then with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel in eluting with the aid of a mixture of toluene/ethyl acetate (95/5; v/v). 11.4 g of the desired product are thus obtained as an oil (yield=87%). nD22=1.564 |
| 87% | With triethylamine In dichloromethane at 0 - 20℃; for 20h; | |
| With triethylamine In dichloromethane at 0 - 20℃; | 193 Et3N (35.96 ml, 256 mmol) was added to a solution of the amine (31.17 g, 213 mmol) in CH2Cl2 (150 ml). Benzyl chloroformate (36.37 ml, 256 mmol) in CH2Cl2 (50 ml) was then added dropwise at a temperature of 0° C. The reaction mixture was stirred overnight at RT and washed with aqueous 0.1 M HCl (150 ml) and H2O (150 ml), dried over Na2SO4 and filtered out, and the solvent was removed in vacuo. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With triethylamine In dichloromethane at 0 - 20℃; for 5h; | CLXXIV A solution of 30.14 g (0.206 M) of 4-[(methylamino)methyl]benzonitrile is prepared in 500 ml of dichloromethane and 22.9 g (0.227 M) of triethylamine are added. The mixture is cooled with the aid of an ice bath and a solution of 41.1 g (0.206 M) of 5-bromopentanoyl chloride in 200 ml of dichloromethane is added dropwise. The reaction mixture is kept under agitation at ambient temperature for 5 hours and then hydrolysed over 300 ml of cold 1N hydrochloric acid. The organic phase is separated, washed with water, and then with a solution of sodium bicarbonate, and then with water and dried over magnesium sulphate. After concentration under reduced pressure, the expected product is obtained as a yellow oil (yield=97%). 1H NMR (300 MHz, DMSO) δ: 7.80 (d, 2H); 7.39 (d, 2H); 4.62 (d, 2H); 3.50 (m, 2H); 2.81 and 2.50 (s, 3H); 2.41 (m, 2H); 1.80 (m, 2H); 1.64 (m, 2H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 71% | With potassium carbonate In acetonitrile at 20 - 55℃; for 18h; Inert atmosphere; | 55.3 Preparation of 4-((methyl((6-phenylimidazo[1,5-a]pyridin-5-yl)methyl)amino)methyl)benzonitrile Compound 489 5-(chloromethyl)-6-phenylimidazo[1,5-a]pyridine 55b (25 mg, 0.103 mmol), 491 4-((methylamino)methyl)benzonitrile (29 mg, 0.2 mmol), 27 K2CO3 (69 mg, 0.5 mmol) and 149 acetonitrile (5 mL) were mixed at room temperature, heated to 55° C. and stirred for 18 h. After cooled to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1 to 1/3) to give the target 492 product 4-((methyl((6-phenylimidazo[1,5-a]pyridin-5-yl)methyl)amino)methyl)benzonitrile 55 (25 mg, light yellow oil). Yield: 71%.MS m/z (ESI): 353[M+1]1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.64-7.42 (m, 7H), 7.38-7.22 (m, 4H), 6.70 (d, J=9.2 Hz, 1H), 3.89 (s, 2H), 3.44 (s, 2H), 2.11 (s, 3H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: norbornane-2-carboxylic acid With thionyl chloride at 70℃; for 1h; Stage #2: methyl-4-cyanobenzylamine In dichloromethane at 20℃; | 2.I.4 I.4) Preparation of N-[(4-cyanophenyl)methyl]-N-methyl-norbornane-2-carboxamide A round-bottom flask was charged with norbornane-2-carboxylic acid (1.0 g, 1 eq.) and thionyl chloride (O.95 g, 2 eq.) was added dropwise. The mixture was warmed to 70° C. for 1 hour. The mixture was cooled to room temperature and dichloromethane (20 mL) was added. Subsequently 4-(methylaminomethyl)benzonitrile (1.03 g, 1.1 eq) was added portion wise. The mixture was stirred at room temperature over night until HPLC indicated complete conversion. The organic layers were washed with hydrochloric acid (1 M), brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the title compound was used directly without further purification. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With Fe3O4(at)CuSiO3 In neat (no solvent) at 100℃; for 16h; Inert atmosphere; | 3.1 General reaction process General procedure: A dried reaction tube equipped with a stir bar was loaded with α-keto acids (0.5 mmol), amine (0.65 mmol),alkyne (0.8 mmol), Fe3O4CuSiO3 (3 mg) under the atmosphere of Ar2 at a ceiling temperature of 90 °C for 16 h. The resulting reaction mixture was loaded on a silica gel column and flashed with 4-10% ethyl acetate inpetroleum ether to afford the desired product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 21% | With nicotinyl chloride hydrochloride In butan-1-ol at 160℃; for 5h; Microwave irradiation; | 39A Step 1: Example (39A): Preparation of Compound 45: 4-(((4-amino-2-butyl-1-methyl- 1H-imidazo[4,5-d]pyridazin-7-yl)(methyl)amino)methyl)benzonitrile A mixture of Intermediate (K) (400 mg,1.67 mmol), 4-(methylaminomethyl)benzonitrile (1.28 g, 8.34 mmol), 1-Butanol (10 mL), 3-chloropyridine hydrochloride (826 mg, 5.51 mmol) were introduced into a microwave vial. The suspension was heated at 160 °C during 5 hours under microwave. The reaction mixture was concentrated under vacuum to give 1.9 g of crude product. This material was dissolved in EtOAc (100 mL) and washed with water (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under vacuum to give 703 mg of yellow solid, which was purified by chromatography on a Merck cartridge (40 g 15-40 µm silica) with a DCM/Methanol/Acetonitrile (96/2/2) elution to afford Example (39A) (124 mg, 21 % yield) as a white solid. 1H NMR (400 MHz, δ in ppm, DMSO-d6): 0.94 (t, J=7.4 Hz, 3 H) ; 1.42 (m, 2 H) ; 1.76 (m, 2 H) ; 2.71 (s, 3 H) ; 2.86 (m, 2 H) ; 4.00 (s, 3 H) ; 4.45 (s, 2 H) ; 6.03 (s, 2 H) ; 7.55 (d, J=8.5 Hz, 2 H) ; 7.76 (d, J=8.5 Hz, 2 H) MS method N: RT (min): 1.12; [M+H]+ 350 |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 17% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 5.1.20.General procedure D for the preparation of final compounds 1a-m, 2a-c, 3a-c, 4a-c, 5a-c General procedure: A mixture of opportune acid (1.2 eq), opportune amine (1 eq), HATU (1 eq) and DIPEA (2.5 eq) was stirred in DMF for 4 h at rt. Then the reaction was quenched in water. If a solid has been formed, it was filtered to obtain the desired compound, otherwise the solution was extracted with ethyl acetate and washed with brine and NaHCO3 saturated solution, the organic phase was concentrated under vacuum and the solid was purified with a column chromatography. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72.5% | With potassium carbonate In acetonitrile at 80℃; for 3h; | 4.2.General procedure for synthesis of compounds 9a-9d, 10a-10m, and 11a-11f General procedure: N-methylbenzylamines or alkyl amine derivatives (1.089 mmol) and K2CO3 (125.4 mg, 0.908 mmol) were added to a suspension of compound 8 (150 mg, 0.363 mmol) in 5 mL of acetonitrile, then refluxed at 80 C for 3 h. The reaction mixture was evaporated to dryness under reduced pressure, and the resultant crude product was purified byumn chromatography on SiO2 (DCM/MeOH (v/v, 3:0.15) to afford the final product 9a-9d, 10a-10g, and 11a-11f with a yield of 52.5-93.6 %. |

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