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Chemical Structure| 78881-21-7 Chemical Structure| 78881-21-7

Structure of 78881-21-7

Chemical Structure| 78881-21-7

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Product Details of [ 78881-21-7 ]

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

Safety of [ 78881-21-7 ]

Computational Chemistry of [ 78881-21-7 ] Show Less

Physicochemical Properties

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

49.81 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.48
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

0.98
Log Po/w (WLOGP)?

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

1.46
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.

1.12
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

1.54
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.32

Water Solubility

Log S (ESOL):?

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

-1.72
Solubility 2.51 mg/ml ; 0.019 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.

-1.61
Solubility 3.21 mg/ml ; 0.0243 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

-2.48
Solubility 0.442 mg/ml ; 0.00334 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

Yes
Log Kp (skin permeation)?

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

-6.41 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

1.0 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)

1.22

Application In Synthesis of [ 78881-21-7 ]

* 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 [ 78881-21-7 ]

[ 78881-21-7 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 96784-54-2 ]
  • [ 78881-21-7 ]
YieldReaction ConditionsOperation 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.

References: [1]Choi-Sledeski, Yong Mi; McGarry, Daniel G.; Green, Daniel M.; Mason, Helen J.; Becker, Michael R.; Davis, Roderick S.; Ewing, William R.; Dankulich, William P.; Manetta, Vincent E.; Morris, Robert L.; Spada, Alfred P.; Cheney, Daniel L.; Brown, Karen D.; Colussi, Dennis J.; Valeria, Chu; Heran, Christopher L.; Morgan, Suzanne R.; Bentley, Ross G.; Leadley, Robert J.; Maignan, Sebastien; Guilloteau, Jean-Pierre; Dunwiddie, Christopher T.; Pauls, Henry W. [Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3572 - 3587].
[2]Current Patent Assignee: NITTO DENKO - US2017/44373, 2017, A1 Location in patent: Paragraph 0227; 0228.
[3]Current Patent Assignee: BAYER PHARMACEUTICALS - US6353006, 2002, B1 Location in patent: Page column 23.
[4]Current Patent Assignee: BRISTOL MYERS SQUIBB - US2005/54655, 2005, A1 Location in patent: Page/Page column 15.
[5]Current Patent Assignee: BRISTOL MYERS SQUIBB - US2004/44203, 2004, A1 Location in patent: Page 27.
[6]Current Patent Assignee: PAHR THERAPEUTICS - US2019/55218, 2019, A1 Location in patent: Paragraph 0307; 0308; 0309.
[7]Velaparthi, Upender; Liu, Peiying; Balasubramanian, Balu; Carboni, Joan; Attar, Ricardo; Gottardis, Marco; Li, Aixin; Greer, Ann; Zoeckler, Mary; Wittman, Mark D.; Vyas, Dolatrai [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3072 - 3076].
[8]Sjogren, Eric B.; Rider, Michael A.; Nelson, Peter H.; Bingham, Stanford; Poulton, Anthony L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 11, p. 3295 - 3301].
[9]Gabriel; Thieme [Chemische Berichte, 1919, vol. 52, p. 1083].
[10]Current Patent Assignee: AVENTIS PHARMACEUTICALS PRODUCTS - US6034093, 2000, A.
[11]Current Patent Assignee: AVENTIS PHARMACEUTICALS PRODUCTS - US6034093, 2000, A.
[12]Current Patent Assignee: ARWENDIE PHARMACY - US5731315, 1998, A.
[13]Current Patent Assignee: SYNTEX USA - US5034410, 1991, A.
  • 3
  • [ 78881-21-7 ]
  • [ 1192152-66-1 ]
YieldReaction ConditionsOperation 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
  • 4
  • [ 28418-88-4 ]
  • [ 36567-04-1 ]
  • [ 78881-21-7 ]
  • [ 1637407-44-3 ]
  • [ 1637407-50-1 ]
YieldReaction ConditionsOperation 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℃;
  • 5
  • [ 78881-21-7 ]
  • [ 19829-79-9 ]
  • [ 2133014-55-6 ]
YieldReaction ConditionsOperation 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.
  • 7
  • [ 78881-21-7 ]
  • [ 890707-29-6 ]
YieldReaction ConditionsOperation 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

 

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