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Product Details of [ 127408-03-1 ]

CAS No. :127408-03-1
Formula : C7H7BrFN
M.W : 204.04
SMILES Code : NC1=CC=C(Br)C(F)=C1C
MDL No. :MFCD09800761
InChI Key :HOFKRNFFIGAFNE-UHFFFAOYSA-N
Pubchem ID :15746684

Safety of [ 127408-03-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 127408-03-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 43.47
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

26.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.91
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

2.4
Log Po/w (WLOGP)?

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

2.91
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.

2.99
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

2.67
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.57

Water Solubility

Log S (ESOL):?

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

-3.06
Solubility 0.177 mg/ml ; 0.000869 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.

-2.59
Solubility 0.527 mg/ml ; 0.00258 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

-3.56
Solubility 0.0558 mg/ml ; 0.000274 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.

-5.84 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)

1.38

Application In Synthesis of [ 127408-03-1 ]

* 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 [ 127408-03-1 ]

[ 127408-03-1 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 443-86-7 ]
  • [ 127408-03-1 ]
YieldReaction ConditionsOperation in experiment
96.91% With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (5 g, 39.95 mmol, 1 equiv.) and DMF (50 mL) and NBS (7.1 g, 39.89 mmol, 0.998 equiv.) was added in three times at 0 °C. Then the resulting solution was stirred ovemight at room temperature and then extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered and the filtrate was concentrated under vacuum to give the title compound as a purple solid in96.91percent yield.
66.7% With N-Bromosuccinimide; In acetonitrile; at 10 - 25℃; for 1h; j0630j To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXI) (50 g, 399 mmol, 1.0 eq) in CH3CN (1.2 L) was added NBS (78 g, 439 mmol, 1.1 eq) in portions at 10°C, the resulting mixture was stirred at 25°C for 1 h. LC/MS showed the reaction was completed. Saturated Na25203 (1.2 L) was then added slowly to the reaction mixture at 10°C, extracted with EtOAc (2 L) and the organic layer was concentrated under vacuum to give cmde product. The residue was washed with PE (1 L), the solid was filtered, washed again with PE (500 mL) and dried under vacuum to give 4-bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXII) as a white solid (163.0 g, 798.9 mmol, 66.7percent yield). ESIMS found C7H7BrFN mlz 204.1 (M+1).
66.7% With N-Bromosuccinimide; In acetonitrile; at 10 - 25℃; for 1h; [0630] To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXI) (50 g, 399 mmol, 1.0 eq) in CCN (1.2 L) was added NBS (78 g, 439 mmol, 1.1 eq) in portions at 10°C, the resulting mixture was stirred at 25°C for 1 h. LC/MS showed the reaction was completed. Saturated Na2S2C>3 ( 1.2 L) was then added slowly to the reaction mixture at 10°C, extracted with EtOAc (2 L) and the organic layer was concentrated under vacuum to give crude product. The residue was washed with PE (1 L), the solid was filtered, washed again with PE (500 mL) and dried under vacuum to give 4-bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXII) as a white solid (163.0 g, 798.9 mmol, 66.7percent yield). ESIMS found C7H7BrFN mlz 204.1 (M+l).
66.7% With N-Bromosuccinimide; In acetonitrile; at 10 - 25℃; for 1h; To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXI) (50 g, 399 mmol, 1.0 eq) in CH3CN (1.2 L) was added NBS (78 g, 439 mmol, 1.1 eq) in portions at 10°C, the resulting mixture was stirred at 25°C for 1 h. LC/MS showed the reaction was completed. Saturated Na2S203 (1.2 L) was then added slowly to the reaction mixture at 10°C, extracted with EtOAc (2 L) and the organic layer was concentrated under vacuum to give crude product. The residue was washed with PE (1 L), the solid was filtered, washed again with PE (500 mL) and dried under vacuum to give 4-bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXII) as a white solid (163.0 g, 798.9 mmol, 66.7percent yield). ESIMS found C7H7BrFN mlz 204.1 (M+l).
66.7% With N-Bromosuccinimide; In acetonitrile; at 25℃; for 1h; To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXI) (50 g, 399 mmol, 1.0 eq) in CCN (1.2 L) was added NBS (78 g, 439 mmol, 1.1 eq) in portions at 10°C, the resulting mixture was stirred at 25°C for 1 h. LC/MS showed the reaction was completed. Saturated Na2S2C>3 ( 1.2 L) was then added slowly to the reaction mixture at 10°C, extracted with EtOAc (2 L) and the organic layer was concentrated under vacuum to give crude product. The residue was washed with PE (1 L), the solid was filtered, washed again with PE (500 mL) and dried under vacuum to give 4-bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXXII) as a white solid (163.0 g, 798.9 mmol, 66.7percent yield). ESIMS found C7H7BrFN mlz 204.1 (M+l).
66.7% With N-Bromosuccinimide; In acetonitrile; at 10 - 25℃; for 1h; To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXIX) (50 g, 399 mmol, 1.0 eq) in CH3CN (1.2 L) was added NBS (78 g, 439 mmol, 1.1 eq) in portions at 10° C., the resulting mixture was stirred at 25° C. for 1 h. LC/MS showed the reaction was completed. Saturated Na2S2O3 (1.2 L) was then added slowly to the reaction mixture at 10° C., extracted with EtOAc (2 L) and the organic layer was concentrated under vacuum to give crude product. The residue was washed with PE (1 L), the solid was filtered, washed again with PE (500 mL) and dried under vacuum to give 4-bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXX) as a white solid (163.0 g, 798.9 mmol, 66.7percent yield). ESIMS found C7H7BrFN m/z 204.1 (M+1).
66.7% With N-Bromosuccinimide; In acetonitrile; at 10 - 25℃; for 1h; Step 1 (0819) To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXIX) (50 g, 399 mmol, 1.0 eq) in CH3CN (1.2 L) was added NBS (78 g, 439 mmol, 1.1 eq) in portions at 10° C., the resulting mixture was stirred at 25° C. for 1 h. LC/MS showed the reaction was completed. Saturated Na2S2O3 (1.2 L) was then added slowly to the reaction mixture at 10° C., extracted with EtOAc (2 L) and the organic layer was concentrated under vacuum to give crude product. The residue was washed with PE (1 L), the solid was filtered, washed again with PE (500 mL) and dried under vacuum to give 4-bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> (XXX) as a white solid (163.0 g, 798.9 mmol, 66.7percent yield). ESIMS found C7H7BrFN m/z 204.1 (M+1).
61% With N-Bromosuccinimide; In acetonitrile; at 10 - 20℃; for 3h; To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (15.0 g, 120 mmol) in ACN (300.0 ml_) was added N-Bromosuccinimide (23 g, 132 mmol) portion wise at 10°C. The reaction mixture was stirred at ambient temperature for 3 h, and was evaporated under reduced pressure. The reaction mixture was diluted with saturated Na2S203 (100.0 ml_) at 10°C and extracted with EtOAc (2 X 100 ml_). Combined organic layer was washed with brine, dried over anhydrous Na2S04 and evaporated under reduced pressure to get desired crude, which was purified by column chromatography^ 00-200 mesh silica gel, eluent: 15percent ethyl acetate in hexane) of the title compound (15 g, 61percent) as a brown solid. LCMS rt 3.27 min MH+204. 1H NMR (400 MHz, DMSO-de) delta 7.09 (t, J=8.2, 1H), 6.40 (d, J=8.52, 1H), 1.98 (s, 3H)
57% To a stirred solution of 3 -fluoro-2- methylaniline (25 g, 200 mmol) in acetic acid (140 mL) at 0-5 0C was added hydrogen bromide (100 mL, 200 mmol) then dimethyl sulfoxide (72 mL) was added slowly dropwise (reaction is exothermic and at temperature higher than 5-15 0C produces dibromoisomer). The mixture was stirred at 5-15 0C for 12 h (mixture became clear solution). The resulting solution was cooled to 0 0C and neutralized with sodium hydroxide then with sodium bicarbonate to pH 7. The mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. Flash chromatography (0-10 percent ethyl acetate in hexane) gave the desired product as a white solid (23.3 g, 114 mmol, 57 percent yield). 1H NMR (400 MHz, CHLOROFORM-J) delta (ppm) 7.11 (t, J=8.20 Hz, IH), 6.35 (d, J=8.98 Hz, IH), 3.72 (br. s., 2H), 2.07 (d, J=I.95 Hz, 3H).
46% With N-Bromosuccinimide; In acetonitrile; at 10 - 20℃; for 0.5h; To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (2.0 g, 16.00 mmol, 1 equiv) in acetonitrile (50 ml_) was added N-bromosuccinamide (3.13 g, 17.60mmol, 1 .1 equiv) portionwise at 10°C. The resulting reaction mixture was stirred at room temperature for 30 min. Upon completion of the reaction, sat Na2S03 (50 ml_) was added slowly into the reaction mixture at 10°C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The residue was triturated with n-pentane to affording the 4-bromo- <strong>[443-86-7]3-fluoro-2-methylaniline</strong> as light yellow solid which was used in the next step without further purification (1 .5g, 46percentyield).LC-MS (ES) m/z = 204.0, 206.0 [M+H]+. NMR (400 MHz, CDCI3) delta ppm 2.10 (s, 3 H), 6.39 (d, J = 8.4 Hz, 1 H), 7.13 (t, J = 8 Hz, 1 H), 7.60 -8.10 (br, 2 H).
With N-Bromosuccinimide; In acetonitrile; at 10 - 20℃; for 0.5h; Example 9; Preparation of 5-Bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate 18)Step 1: 4-Bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> To a solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (20 g, 0.16 mol) in CH3CN (500 mL) was added NBS (31.3 g, 0.176 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether affording the title compound (20 g), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): delta 7.08 (t, 1H), 6.40 (dd, 1H), 5.35 (br, 2H), 1.98 (d, 3H).
With N-Bromosuccinimide; In acetonitrile; at 10 - 20℃; for 0.5h; To a solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (20 g, 0.16 mol) in CH3CN (500 mL) was added NBS (31.3 g, 0.176 mol) in portions at 10 °C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10 °C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether affording the title compound (20 g), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): oe 7.08 (t, 1H), 6.40 (dd, 1H), 5.35 (br, 2H), 1.98 (d, 3H).
With N-Bromosuccinimide; In acetonitrile; at 0 - 10℃; for 0.5h; 10292] To a stirred solution of <strong>[443-86-7]3-fluoro-2-methylaniline</strong> (15 g, 0.1199 mol) in acetonitrile (300 mE) was added N-bromo succinamide (23.5 g, 0.131 mol) at 0° C. The reaction mixture was stirred for 30 mm at 100 C., after completion of reaction (monitored by TEC), the reaction mixture was diluted with EtOAc. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was used in next step without further purification to afford 4-bromo-<strong>[443-86-7]3-fluoro-2-methylaniline</strong> (25g, crude) as a white solid.
With N-Bromosuccinimide; In acetonitrile; at 25℃; for 2h; Into a 250-mL a round bottle were placed <strong>[443-86-7]3-fluoro-2-methylbenzenamine</strong> (2.00 g, 15.982 mmol, 1.00 equiv.), NBS (2.99 g, 16.798 mmol, 1.051 equiv.), MeCN (100 mL). The resulting solution was stirred 2 h at 25° C. The reaction was then quenched by H2O. The resulting solution was extracted with EA and the organic layers combined and concentrated under vacuum. The residue was purified by silica gel column with PE:EA=70:30 to yield 4-bromo-<strong>[443-86-7]3-fluoro-2-methylbenzenamine</strong> as yellow solid. Mass spectrum (EI, m/z): Calculated for C7H7BrFN, 203.0 [M], found 202.9.
With N-Bromosuccinimide; In acetonitrile; at 25℃; for 2h; Into a 250-mL a round bottle were placed <strong>[443-86-7]3-fluoro-2-methylbenzenamine</strong> (2.00 g, 15.982 mmol, 1.00 equiv.), NBS (2.99 g, 16.798 mmol, 1.051 equiv.), MeCN (100 mL). The resulting solution was stirred 2 h at 25° C. The reaction was then quenched by H2O. The resulting solution was extracted with EA and the organic layers combined and concentrated under vacuum. The residue was purified by silica gel column with PE:EA=70:30 to yield 4-bromo-<strong>[443-86-7]3-fluoro-2-methylbenzenamine</strong> as yellow solid. Mass spectrum (EI, m/z): Calculated for C7H7BrFN, 203.0 [M], found 202.9.

 

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