Structure of 90389-96-1
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| CAS No. : | 90389-96-1 |
| Formula : | C9H10N2 |
| M.W : | 146.19 |
| SMILES Code : | N#CC1=CC=CC(CNC)=C1 |
| English Name : | 3-((Methylamino)methyl)benzonitrile |
| MDL No. : | MFCD09731650 |
| InChI Key : | KBRCDVSFCMVQSN-UHFFFAOYSA-N |
| Pubchem ID : | 457595 |
| 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 |
1.94 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-4.5 |
| 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 |
0.31 |
| Log S (ESOL):? ESOL: Topological method implemented from |
1.82 |
| Solubility | 9590.0 mg/ml ; 65.6 mol/l |
| Class? Solubility class: Log S scale |
Highly soluble |
| Log S (Ali)? Ali: Topological method implemented from |
4.37 |
| Solubility | 3400000.0 mg/ml ; 23200.0 mol/l |
| Class? Solubility class: Log S scale |
Highly 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 |
-10.39 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 |
2.0 |
| 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) |
1.25 |
* 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 |
|---|---|---|
| 100% | In THjfF (tetrahydrofuran) at 20℃; for 3h; Inert atmosphere; | 42.1 Step 1: 3-[(methylamino)methyllbenzonitrileIn a 3 necked round bottom flask (250 ml), put under nitrogen atmosphere, a solution of 3- (bromomethyl)benzonitrile (5 g; 25.5 mmol; 1 eq.) in anhydrous THF (20 ml) was added dropwise into methylamine (63.76 ml; 2 M; 127.52 mmol; 5 eq.) (2M solution in THF) over 1 hour. The reaction mixture was stirred at RT for 2 hours. Some bis-benzylation was observed (7%). The reaction mixture was filtered to remove the salt. The filtrate was evaporated under reduced pressure. The residue was taken up with DCM and evaporated again to give the title compound as a yelllow oil (3.78 g, quantitative yield). It was used in the next step without any further purification. LC/MS (Method B) 146.8 (M+H)+. |
| 96% | In tetrahydrofuran at 20℃; for 24h; | 49 To a commercially available solution of methylamine 2M in tetrahydrofuran (200 ml, 400 mmol), 11.2 g (57.1 mmol) of 3-(bromomethyl)benzonitrile dissolved in 112 ml of tetrahydrofuran were added dropwise. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The obtained residue was diluted with ethyl ether and extracted with 1 N HCI. The acidic extracts were basified with solid potassium carbonate and the basic solution extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The title compound was obtained as an oil (7.98g, 96%). |
| 82% | In water at 0 - 20℃; for 3.16h; | 62.1 To a stirred solution of methylamine(40% in water) (200 ml_) under N2, was added 3-(bromomethyl)benzonitrile (10 g, 0.051 mol) slowly in small portions over a period of 10min at O0C. After being stirred at RT for 3h, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The obtainted crude was purified using column chromatography on silica gel (pet ether/ehyl acetate) to afford the title compound as a pale yellow liquid (6.1 g, 82%). 1H NMR (DMSO-de, 400 MHz) δ 7.74 (s, 1 H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1 H), 3.66 (s, 2H), 2.22 (s, 3H). |
| 82% | In water at 0 - 20℃; for 3.16667h; | 16.1 To a stirred solution of methylamine (40% in water, 200 mL) under N2, was added 3- (bromomethyl)benzonitrile (10 g, 51 mmol) slowly in portions over 10 minutes at O0C. After being stirred at RT for 3 hours, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford the title compound as a pale yellow liquid (6.1 g, 82%). 1H NMR (DMSOd6, 400 MHz) δ 7.74 (s, 1 H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1 H), 3.66 (s, 2H), 2.22 (s, 3H). |
| With benzene | ||
| In ethanol for 6h; | ||
| In methanol for 1h; Heating / reflux; | H.2.2 Step 2 : A-BROMO-M-CYANOTOLUENE (1.0 g, 5.1 mmol) in 2M MeNH2/MeOH (25. 5 mL, 51 mmol) was refluxed for lh. After evaporating most of solvent, the resulting solid was filtered. The mother liquor was concentrated in vacuo and it was purified by chromato- GRAPHY. | |
| In acetonitrile at 20℃; for 0.5h; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | Stage #1: 3-Cyanobenzaldehyde; methylamine With titanium(IV) isopropylate In methanol at 20℃; for 5h; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 2h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 57% | With potassium hydroxide In isopropyl alcohol for 2h; Heating / reflux; | 50 To a solution of 7.98 g (54.6 mmol) of Intermediate 49 in 80 ml of isopropanol, 7.98 g (142.2 mmol) of powdered KOH (85%) were added. The mixture was stirred for 2 hours at reflux temperature. The solvent was reduced under reduced pressure. The obtained residue was dissolved in a small volume of water and extracted several times with dichloromethane. The organic extracts were combined, dried (MgSO4), and concentrated. The residue was treated with hexane and concentrated (x3). The obtained residue was treated with chloroform and concentrated (x3), and finally the residual solvents were eliminated using an oil vacuum pump. The title compound was obtained as an oil that slowly solidified at room temperature. (5.14 g, 57%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With N-ethyl-N,N-diisopropylamine In ethanol at 120℃; for 1.5h; | B.2; H.2.1 Example B-2: 3- { [ (6, 7-DIMETHOXY-5-METHYL-4-OXO-L, 4-dihydro-quinazolin-2-yl) - methyl-amino]-methyl}-benzonitrile DIISOPROPYLETHYLAMINE (0.82 mL, 4.71 mmol) was added to a mixture of 2-chloro-6, 7- dimethoxy-5-methylquinazolin-4-one (1.0 g, 3.92 mmol) AND N METHYL- (3-CYANO- benzyl) -amine (0.68 g, 4.71 mmol) in ETOH (50 mL). The mixture was heated at 120°C for 1.5 h in a sealed tube. After cooling, the resulting white solid was filtered and washed with MEOH to provide the arylnitrile of Example B-2. Mp 279.9-281. 5 °C ; 1H NMR (DMSO-d6) 6 2.6 (s, 3H), 3.05 (s, 3H), 3.62 (s, 3H), 3. 84 (s, 3H), 4.86 (s, 2H), 6.62 (s, 1H), 7.5-7. 7. 78 (m, 4H) ; 13C NMR (DMSO-D6) 5 13.89, 35. 58, 51.52, 55.93, 60.22, 104. 79,111. 78, 119.15, 130. 12, 131. 19, 131.28, 131.96, 132.51, 140.04, 142.96, 150.51, 157. 71. MW=365.; DIISOPROPYLELYLAMINE (0.82 ML, 4.71 MMOL) WAS ADDED TO THE MIXTURE OF 2- chloro-6,7-dimethoxy-5-methyl-quinazolin-4-one (1.0 g, 3.92 mmol) and N-methyl-(3- cyano-benzyl) -amine (0.68 g, 4.71 mmol) in ETOH (50 mL). It was heated at 120°C for 1.5h in the sealed tube. After cooling down, the resulting white solid was filtered and washed with MEOH : mp 279.9-281. 5°C ; 1H NMR (DMSO-d6) 8 2.6 (s, 3H), 3.05 (s, 3H), 3.62 (s, 3H), 3.84 (s, 3H), 4.86 (s, 2H), 6.62 (s, 1H), 7.5-7. 7. 78 (m, 4H) ; 13C NMR (DMSO-d6) 8 13. 89,35. 58,51. 52,55. 93,60. 22,104. 79,111. 78,119. 15,130. 12,131. 19, 131. 28, 131.96, 132.51, 140.04, 142.96, 150.51, 157. 71; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium hydrogencarbonate In acetonitrile at 20℃; for 12h; | 62.2 To a stirred solution of 3-[(methylamino)methyl]benzonitrile(6.1 g, 0.0417 mol) and sodium bicarbonate (7 g, 0.0834 mol) in acetonitrile (70 ml_) under N2, was added tert-butyl-3-bromo- propanoate (7 ml_, 0.0417 mol) in dropwise. After being stirred at RT for 12h, the reaction mixture was filtered and the filterate was concentrated under reduced pressure. The obtainted crude was purified using column chromatography on neutral silica gel (pet ether/EtOAc) to afford the title compound as a pale yellow liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.69-7.70 (s, 2H), 7.59-7.61 (m, 1 H), 7.49-7.53 (m, 1 H), 3.49 (s, 2H), 2.56-2.59 (m, 2H), 2.34-2.38 (m, 2H), 2.09 (s, 3H), 1.38 (s, 9H). | |
| With sodium hydrogencarbonate In acetonitrile at 20℃; for 12h; | 16.2 To a stirred mixture of 3-[(methylamino)methyl]benzonitrile (6.1 g, 41.7 mmol) and sodium bicarbonate (7.0 g, 83.4 mmol) in ACN (70 mL) was added dropwise tert-butyl 3-bromo- propanoate (7 mL, 41.7 mol). After being stirred at RT for 12 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford the title compound as a pale yellow liquid. 1H NMR (DMSOd6, 400 MHz) δ 7.70 (s, 2H), 7.60 (m, 1 H), 7.51 (m, 1 H), 3.49 (s, 2H), 2.58 (m, 2H), 2.36 (m, 2H), 2.09 (s, 3H), 1.38 (s, 9H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 79% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; Reflux; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | In dichloromethane at 0 - 20℃; for 0.533333h; Cooling with ice; | 42.2 Step 2: tert-butyl (3-cyanobenzyl)methylcarbamateIn a round bottom flask (100 ml), put under nitrogen atmosphere, a solution of crude 3-[(methylamino)methyl]benzonitrile (3.78 g; 23.79 mmol; 1 eq.) in DCM (37.80 ml) was prepared and cooled in an ice bath, then a solution of di-tert-butyl dicarbonate (5.19 g; 23.79 mmol; 1 eq.) in DCM (18.90 ml) was added over 2 minutes. The reaction mixture was stirred between 0°C and RT during 30 min. The reaction mixture was concentrated under reduced pressure to give a yellow oil (6.87 g). It was purified by flash chromatography (heptane / EtOAc gradient from 90:10 up to 70:30), affording the title compound as a colorless oil (5.13 g, 88%). 1H NMR (DMSO-de, 300 MHz) δ 7.76 (ddd, J = 6.9, 1 .9, 1 .8, 1 H), 7.65 (s, 1 H), 7.62 - 7.48 (m, 2H), 4.41 (s, 2H), 2.79 (s, 3H), 1 .62 - 1.16 (m, 9H). HPLC (Method A) Rt 4.28min (Purity: 100.0%). |
| 0.8 g | With triethylamine In dichloromethane at 0 - 20℃; for 0.5h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77% | With potassium carbonate; potassium iodide In acetonitrile at 130℃; for 0.5h; Microwave irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 56% | Stage #1: 7-(3-(bromomethyl)benzyloxy)coumarin; 3-((methylamino)methyl)benzonitrile With potassium carbonate In acetonitrile at 130℃; for 0.5h; Microwave irradiation; Stage #2: With hydrogenchloride In 1,4-dioxane |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 60% | Stage #1: 7-[4-(bromomethyl)benzyl]oxy}-3,4-dimethyl-2H-chromen-2-one; 3-((methylamino)methyl)benzonitrile With potassium carbonate In acetonitrile at 130℃; for 0.5h; Microwave irradiation; Stage #2: With hydrogenchloride In 1,4-dioxane |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 57% | With triethylamine In tetrahydrofuran at 0 - 25℃; for 3h; | 3 Example 3: 3-(((4-Chloro-3-oxo-3H-l,2-dithiol-5-yl)(methyl)amino)methyl)benzonitrile (Compound 88) To a stirred solution of 4,5-dichloro-3H-l,2-dithiol-3-one (500 mg, 2.67 mmol) in tetrahydrofuran (10 mL), 3-((methylamino)methyl)benzonitrile (391 mg, 2.67 mmol) and triethylamine (0.45 mL, 3.21 mmol) were added at 0 °C. The reaction was allowed to stir at 25 °C for 3 h. Water was added to the reaction mixture and the product was extracted twice with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was then purified by column chromatography on silica gel (eluent-hexane to 30 % ethyl acetate in hexane) to obtain 3-(((4-chloro-3-oxo-3H-l,2-dithiol-5- yl)(methyl)amino)methyl)benzonitrile (455 mg, 1.53 mmol, 57 % yield). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 87% | With sodium phenyltrihydroxyborate; phenylsilane In diethylene glycol dimethyl ether at 60℃; for 12h; Sealed tube; Glovebox; Autoclave; | |
| 99 % | With phenylsilane In tetrahydrofuran at 80℃; Autoclave; Green chemistry; chemoselective reaction; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 4.95 % | With triethylamine In dichloromethane at 25℃; | 2.106 Example 106: N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N- methylpyridine-3-sulfonamide To a chloride (Intermediate 57) (50 mg, 0.191 mmol) and 3-((methylamino)methyl)benzonitrile (33.5 mg, 0.229 mmol) in dichloromethane (0.1 mL) was added triethylamine (58.0 mg, 0.573 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 20 minutes. The mixture was poured into water (10 mL) and extracted with dichloromethane (3 x 10 mL), the combined organic layers were concentrated to afford the crude product which was purified by prep. HPLC (Column: Xtimate C18 100*30mm*10μm, Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 50% B to 80%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3- sulfonamide (3.53 mg, 0.009 mmol, 4.95% yield) as an off-white gum. 1H NMR (400MHz, DMSO-d6): 8.62 (d, J = 3.0 Hz, 1H), 8.32 (dd, J = 2.9, 7.4 Hz, 1H), 7.98 - 7.67 (m, 3H), 7.67 - 7.59 (m, 2H), 4.45 (s, 2H), 2.83 (s, 3H); MS ES+: 372.2 |
| 4.95 % | With triethylamine In dichloromethane at 25℃; | 2.106 Example 106: N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N- methylpyridine-3-sulfonamide To a chloride (Intermediate 57) (50 mg, 0.191 mmol) and 3-((methylamino)methyl)benzonitrile (33.5 mg, 0.229 mmol) in dichloromethane (0.1 mL) was added triethylamine (58.0 mg, 0.573 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 20 minutes. The mixture was poured into water (10 mL) and extracted with dichloromethane (3 x 10 mL), the combined organic layers were concentrated to afford the crude product which was purified by prep. HPLC (Column: Xtimate C18 100*30mm*10μm, Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 50% B to 80%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3- sulfonamide (3.53 mg, 0.009 mmol, 4.95% yield) as an off-white gum. 1H NMR (400MHz, DMSO-d6): 8.62 (d, J = 3.0 Hz, 1H), 8.32 (dd, J = 2.9, 7.4 Hz, 1H), 7.98 - 7.67 (m, 3H), 7.67 - 7.59 (m, 2H), 4.45 (s, 2H), 2.83 (s, 3H); MS ES+: 372.2 |
| 4.95 % | With triethylamine In dichloromethane at 25℃; | 2.106 Example 106: N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N- methylpyridine-3-sulfonamide To a chloride (Intermediate 57) (50 mg, 0.191 mmol) and 3-((methylamino)methyl)benzonitrile (33.5 mg, 0.229 mmol) in dichloromethane (0.1 mL) was added triethylamine (58.0 mg, 0.573 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 20 minutes. The mixture was poured into water (10 mL) and extracted with dichloromethane (3 x 10 mL), the combined organic layers were concentrated to afford the crude product which was purified by prep. HPLC (Column: Xtimate C18 100*30mm*10μm, Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 50% B to 80%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3- sulfonamide (3.53 mg, 0.009 mmol, 4.95% yield) as an off-white gum. 1H NMR (400MHz, DMSO-d6): 8.62 (d, J = 3.0 Hz, 1H), 8.32 (dd, J = 2.9, 7.4 Hz, 1H), 7.98 - 7.67 (m, 3H), 7.67 - 7.59 (m, 2H), 4.45 (s, 2H), 2.83 (s, 3H); MS ES+: 372.2 |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 63.5% | With potassium carbonate In acetonitrile at 80℃; | 4.4.General procedure for synthesis of compounds 11a-11m General procedure: To a suspension of compound 9 (150 mg, 0.363 mmol, 1 equiv.) in acetonitrile (5 mL) was added N-methylbenzylamine derivatives (10a-10m, 1.089 mmol, 3 equiv.) and K2CO3 (125.4 mg, 0.908 mmol, 2.5 equiv.). The reaction mixture was refluxed at 80 C for 4 h, then cooled to room temperature, filtered, and concentrated under reduced pressure, and the crude residue was purified by column chromatography on SiO2, eluted with DCM/MeOH (v/v, 3:0.15) to give 11a-11m. |

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