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Chemical Structure| 1147558-43-7

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Product Details of [ 1147558-43-7 ]

CAS No. :1147558-43-7
Formula : C7H4ClFN2
M.W : 170.57
SMILES Code : N#CC1=CC(F)=C(N)C(Cl)=C1
MDL No. :MFCD18426013
InChI Key :BWAFIBAPFADXHV-UHFFFAOYSA-N
Pubchem ID :68039995

Safety of [ 1147558-43-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 1147558-43-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
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.

1.49
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

1.69
Log Po/w (WLOGP)?

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

2.36
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.

1.82
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

2.15
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.9

Water Solubility

Log S (ESOL):?

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

-2.37
Solubility 0.735 mg/ml ; 0.00431 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.35
Solubility 0.76 mg/ml ; 0.00446 mol/l
Class?

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

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

-3.01
Solubility 0.165 mg/ml ; 0.000968 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.

-6.14 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)

1.77

Application In Synthesis of [ 1147558-43-7 ]

* 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 [ 1147558-43-7 ]

[ 1147558-43-7 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 63069-50-1 ]
  • [ 1147558-43-7 ]
YieldReaction ConditionsOperation in experiment
88% With N-chloro-succinimide; In acetonitrile; at 85℃; for 5.0h; 4-Amino-3-chloro-5-fluorobenzonitrile A mixture of 4-amino-3-fluorobenzonitrile (1 equiv.) and N-chlorosuccinimide (1.5 equiv.) in acetonitrile (0.24 M) was stirred at 85 C. for 5 h. The solvent was removed by concentration and the residue was partitioned between ethyl acetate and 5% NaOH. The organic phase was washed with 5% NaOH and brine. Then the organic phase was dried over MgSO4 and dried in vacuum to afford 4-amino-3-chloro-5-fluorobenzonitrile (88%) as a beige solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.41 (t, J=6 Hz, 1H), 7.24 (dd, J=1.8, 10.2 Hz, 1H), 4.66 (s, 2H).
With N-chloro-succinimide; In acetonitrile; at 86℃; for 6.0h; INTERMEDIATE 74-Amino-3-chloro-5-fluorobenzonitrile A solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86 C (reflux) for 5 h. LCMS showed -17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2S04 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H20 and air dried to give the desired product as a beige solid. This product was used in the next step without any futher purification. MS (m/z) 171.1 (M+H+).
With N-chloro-succinimide; In acetonitrile; at 86℃; for 6.0h; 4-Amino-3-chloro-5-fluorobenzonitrileA solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86 C (reflux) for 5 h. LCMS showed -17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2S04 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H20 and air dried to give the desired product as a beige solid. This product was used in the next step without any futher purification. MS (m/z) 171.1 (M+H+).
With N-chloro-succinimide; acetic acid; at 70℃; for 16.0h; 1.13. Synthesis of 4-amino-3-chloro-5-fluoro-benzonitrile (Int.21) A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70 C. for approximately 16 h. The mixture was concentrated. H2O was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H2O). To eliminate H2O, THF was added and removed under reduced pressure to yield the desired product.
With N-chloro-succinimide; acetic acid; at 70℃; for 16.0h; 1.13. Synthesis of 4-amino-3-chloro-5-fluoro-benzonitrile (mt. 21) j00260j A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70C for approximately 16 h. The mixture was concentrated. H20 was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H20). To eliminate H20, THF was added and removed under reduced pressure to yield the desired product.
With N-chloro-succinimide; acetic acid; at 70℃; for 0.16h; A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mE) was stirred at 70 C. for approximately 16 h. The mixture was concentrated. H20 was added to the residue and the solid product was filtered oil and washed (sat. NaHCO3 and H20). To eliminate H20, THF was added and removed under reduced pressure to yield the desired product.
With N-chloro-succinimide; In acetic acid; at 70℃; for 16.0h; 3.123. Compound 111: (lR,2R)-N-[6-(2-chloro-4-cyano-6-fluoro-N-methyl-anilino)-l-methyl- 3.123.1. Step i): 4-amino-3-chloro-5-fluoro-benzonitrile A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) is stirred at 70C for approximately 16 h. The mixture is concentrated. H20 is added to the residue and the solid product is filtered off and washed (sat. NaHCC>3 and H20). To eliminate H20, THF is added and removed under reduced pressure to yield the desired product (Int. 21). 3.123.2. Step ii): 4-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(methylamino)-5-nitro-2- pyridyl]amino]-3-chloro-5-fluoro-benzonitrtte

  • 2
  • [ 1147558-43-7 ]
  • [ 1273585-10-6 ]
YieldReaction ConditionsOperation in experiment
81% With sodium perborate tetrahydrate; acetic acid; In water; acetic acid; at 20 - 80℃; for 73.0h; [0146] Sodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60 C. A solution of<strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (29.0 g, 170 mmol) in acetic acid (500 mL) was added dropwise, and the resultingreaction was stirred at 60C for 18 h. LCMS analysis indicated -50 % conversion. Additional sodium perborate tetrahydrate(14.4 g, 93.6 mmol) was added, and the reaction was stirred at 70C for 2 h followed by another addition of sodiumperborate tetrahydrate (70.0 g, 455 mmol). The reaction was stirred at 80 C for 5 h and then at rt for 2 d. The reactionwas poured into ice water, and the product was extracted into EtOAc. The combined organics were washed with waterand brine. Finally, the organics were dried over MgSO4, filtered, and concentrated to half volume. Addition of waterresulted in precipitation of the desired product which was collected in a frit, washed with water, and dried in vacuo toprovide an orange solid (27.5 g, 81 % crude yield). 1H NMR (400 MHz, CDCl3) delta 7.68 (s, 1H), 7.55 (d, 1 H).
With sodium perborate; acetic acid; at 20 - 80℃; for 71.0h; 3-Chloro-5-fluoro-4-nitrobenzonitrile Sodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60 C. A solution of <strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (29.02 g, 170 mmol) in acetic acid (500 ml.) was added dropwise and the reaction was stirred at 60 C for 16 h. The LCMS the indicated the reaction showed -50% conversion. Additional sodium perborate tetrahydrate (14.4 g) was added and the reaction stirred at 70 C for 2 h. Then additional sodium perborate tetrahydrate (70 g) was added and the reaction was stirred at 80 C for 5 h, followed by RT for 2 days. The reaction was then poured into ice water and extracted with EtOAc (3x). The combined organic extracts were washed with H20 (2x), brine, dried over MgS04 and concentrated. When most of the acetic acid was evaporated, water was added to the residue. The orange precipitate was collected by filtration, washed with H20 and air dried to give the crude product as an orange solid. NMR showed the product contaminated with -10% of starting material. This product was used without any further purification.
With sodium perborate tetrahydrate; acetic acid; at 20 - 80℃; for 71.0h; 3-Chloro-5-fluoro-4-nitrobenzonitrileSodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60 C. A solution of <strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (29.02 g, 170 mmol) in acetic acid (500 mL) was added dropwise and the reaction was stirred at 60 C for 16 h. The LCMS the indicated the reaction showed -50% conversion. Additional sodium perborate tetrahydrate (14.4 g) was added and the reaction stirred at 70 C for 2 h. Then additional sodium perborate tetrahydrate (70 g) was added and the reaction was stirred at 80 C for 5 h, followed by RT for 2 days. The reaction was then poured into ice water and extracted with EtOAc (3x). The combined organic extracts were washed with H20 (2x), brine, dried over MgS04 and concentrated. When most of the acetic acid was evaporated, water was added to the residue. The orange precipitate was collected by filtration, washed with H20 and air dried to give the crude product as an orange solid. NMR showed the product contaminated with -10% of starting material. This product was used without any further purification. 4-Chloro-1-r(3S,5S)-1-oxaspiror2.5loct-5-ylmethyll-1 H-benzimidazole-6-carbonitrile
  • 3
  • [ 463-71-8 ]
  • [ 1147558-43-7 ]
  • 3-chloro-5-fluoro-4-isothiocyanatobenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% With N-ethyl-N,N-diisopropylamine; at 0 - 20℃; 3-Chloro-5-fluoro-4-isothiocyanatobenzonitrile To a mixture of <strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (1 equiv.) and DIEA (3.5 equiv.) in DCM (1 M) was added thiophosgene (3.5 equiv.) at 0 C. The reaction was stirred at room temperature overnight. The solvent was removed and the residue was purified by preparative TLC to give 3-chloro-5-fluoro-4-isothiocyanatobenzonitrile (34%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.55 (t, J=1.6 Hz, 1H), 7.40 (dd, J=1.7, 8.5 Hz, 1H).
  • 4
  • [ 1147558-43-7 ]
  • (1s,4s)-4-((5-(3-(2-chloro-4-cyano-6-fluorophenyl)thioureido)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide [ No CAS ]
  • 5
  • [ 1147558-43-7 ]
  • (1s,4s)-4-(8-(2-chloro-4-cyano-6-fluorophenylamino)-2-(tetrahydro-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide [ No CAS ]
  • 6
  • [ 1147558-43-7 ]
  • 3-chloro-5-(((-7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile [ No CAS ]
  • 7
  • [ 1147558-43-7 ]
  • 4-chloro-1-((-7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile trifluoroacetic acid salt [ No CAS ]
  • 8
  • [ 1147558-43-7 ]
  • 6-chloro-N2,N2-bis(4-methoxybenzyl)-N4-methyl-3-nitropyridine-2,4-diamine [ No CAS ]
  • 4-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(methylamino)-5-nitro-2-pyridyl]amino]-3-chloro-5-fluorobenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 16.0h; 3.123.2. Step ii): 4-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(methylamino)-5-nitro-2- pyridyl]amino]-3-chloro-5-fluoro-benzonitrtte A mixture of 6-chloro-N2,N2-bis[(4-methoxyphenyl)methyl]-N4-methyl-3-nitro-pyridine-2,4- diamine (3.39 mmol), <strong>[1147558-43-7]4-amino-3-chloro-5-fluoro-benzonitrile</strong> (6.78 mmol) and CS2CO3 (13.6 mmol) in DMA (15 mL) is stirred for 16 h at 120 C. A solution of saturated NH4C1 is added to the mixture. The solid is filtered out and further washed with water. The solid is taken up in EtOAc and the organic mixture is washed (H20 and brine), dried (Na2S04) and concentrated. The residue is purified by flash column chromatography (S1O2, 100:0 to 50:50 petroleum ether/EtOAc) to afford the desired product.
  • 9
  • [ 1147558-43-7 ]
  • 6-chloro-N2,N2-bis(4-methoxybenzyl)-N4-methyl-3-nitropyridine-2,4-diamine [ No CAS ]
  • 4-[[4-[bis[(4-methoxyphenyl)methyl]amino]-1-methylimidazo[4,5-c]pyridin-6-yl]amino]-3-chloro-5-fluorobenzonitrile [ No CAS ]
 

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