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Chemical Structure| 34403-48-0 Chemical Structure| 34403-48-0

Structure of 34403-48-0

Chemical Structure| 34403-48-0

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Product Details of [ 34403-48-0 ]

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

Safety of [ 34403-48-0 ]

Computational Chemistry of [ 34403-48-0 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

35.82 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.93
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.95
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.13
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.17
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.81
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.4

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.62
Solubility 3.54 mg/ml ; 0.0242 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.29
Solubility 7.51 mg/ml ; 0.0514 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.31
Solubility 0.0724 mg/ml ; 0.000495 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.52 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.18

Application In Synthesis of [ 34403-48-0 ]

* 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.

  • Downstream synthetic route of [ 34403-48-0 ]

[ 34403-48-0 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 17201-43-3 ]
  • [ 74-89-5 ]
  • [ 34403-48-0 ]
YieldReaction ConditionsOperation 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.

  • 2
  • [ 118964-95-7 ]
  • [ 34403-48-0 ]
YieldReaction ConditionsOperation 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;

  • 3
  • [ 24424-99-5 ]
  • [ 34403-48-0 ]
  • [ 191871-90-6 ]
YieldReaction ConditionsOperation 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).
  • 4
  • [ 34403-48-0 ]
  • [ 501-53-1 ]
  • [ 441295-89-2 ]
YieldReaction ConditionsOperation 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.
  • 5
  • [ 4509-90-4 ]
  • [ 34403-48-0 ]
  • [ 633699-38-4 ]
YieldReaction ConditionsOperation 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).
  • 6
  • [ 34403-48-0 ]
  • [ 2192265-11-3 ]
  • [ 2192264-46-1 ]
YieldReaction ConditionsOperation 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).
  • 7
  • [ 824-62-4 ]
  • [ 34403-48-0 ]
  • [ 2181644-76-6 ]
YieldReaction ConditionsOperation 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.
  • 8
  • [ 34403-48-0 ]
  • [ 536-74-3 ]
  • [ 611-73-4 ]
  • [ 2400925-31-5 ]
YieldReaction ConditionsOperation 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.
  • 9
  • [ 34403-48-0 ]
  • [ 2817602-59-6 ]
  • [ 2817601-10-6 ]
YieldReaction ConditionsOperation 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
  • 10
  • [ 34403-48-0 ]
  • [ 152827-50-4 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation 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.
  • 11
  • [ 1189553-74-9 ]
  • [ 34403-48-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation 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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Technical Information

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