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Structure of 38267-96-8

Chemical Structure| 38267-96-8

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Product Details of [ 38267-96-8 ]

CAS No. :38267-96-8
Formula : C8H4BrClN2
M.W : 243.49
SMILES Code : BrC2=CC=C1N=CN=C(C1=C2)Cl
MDL No. :MFCD01862191

Safety of [ 38267-96-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 38267-96-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 10
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 52.25
TPSA ?

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

25.78 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.29
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

3.19
Log Po/w (WLOGP)?

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

3.05
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.

2.58
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

3.25
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.87

Water Solubility

Log S (ESOL):?

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

-3.98
Solubility 0.0257 mg/ml ; 0.000106 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.

-3.4
Solubility 0.0963 mg/ml ; 0.000396 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

-4.8
Solubility 0.00384 mg/ml ; 0.0000158 mol/l
Class?

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

Moderately 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.

-5.52 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

0.0
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)

1.48

Application In Synthesis of [ 38267-96-8 ]

* 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 [ 38267-96-8 ]

[ 38267-96-8 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 38267-96-8 ]
  • [ 35216-39-8 ]
  • 6-bromo-N-[3-(methylsulfonyl)phenyl]-4-quinazolinamine [ No CAS ]
  • 2
  • [ 38267-96-8 ]
  • [ 35216-39-8 ]
  • N-[3-(methylsulfonyl)phenyl]-6-(1,3-thiazol-5-yl)-4-quinazolinamine [ No CAS ]
  • 3
  • [ 88675-24-5 ]
  • [ 38267-96-8 ]
  • 6-bromo-N-(tetrahydro-3-furanyl)-4-quinazolinamine [ No CAS ]
  • 4
  • [ 38267-96-8 ]
  • [ 1228947-14-5 ]
  • 4-((1r,4r)-4-((6-bromoquinazolin-4-yl)oxy)cyclohexyl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% To a solution of trans-4-(morpholin-4-yl)cyclohexan-l-ol, compound 4.1 (364 mg, 1.96 mmol, 1.20 equiv) in distilled THF (10 mL) was added NaHDMS (2.45 mL, 3.00 equiv, 2 M in THF) dropwise via syringe at 0 C under nitrogen. Subsequently a solution of 6-bromo-4- chloroquinazoline (400 mg, 1.64 mmol, 1.00 equiv) in THF (5 mL) was added slowly at 0C and the reaction was stirred for 1 hour at this temperature. The reaction was then quenched with saturated aqueous NH4C1, extracted with 3 x 60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to furnish 357 mg (55%) of 4- ((lr,4r)-4-((6-bromoquinazolin-4-yl)oxy)cyclohexyl)morpholine, 1-4, as a white solid. LCMS (ES, m/z): 393 [M+H]+; 1H NMR (300 MHz, CD3OD) delta 8.75 (s, 1H), 8.30 (d, 1H), 8.02 (dd, 1H), 7.80 (d, 1H), 5.40-5.30 (m, 1H), 3.73 (t, 4H), 2.64 (t, 4H), 2.42-2.35 (m, 3H), 2.12 (d, 2H), 1.78- 1.60 (m, 2H), 1.58-1.49 (m, 2H).
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 18h; Trans-4-morpholinocyclohexanol (0.134 g, 0.723 mmol) was dissolved in THF (10.95 ml) and added to a slurry of 6-bromo-4-chloroquinazoline (0.16 g, 0.657 mmol) in N,N- dimethylformamide (0.349 mL). The reaction was cooled to 0 C and sodium hydride (0.053 g, 1.31 mmol) was added to the reaction mixture at 0 C and the reaction was allowed to stir at rt for 18 h. The reaction was quenched with saturated aqeuous sodium bicarbonate and the aqueous layer was extracted with 25% IPA/CHCI3 (2x), dried over anhydrous sodium sulfate, filtered and purified by mass triggered reverse phase HPLC (ACN/water with 0.1% NH4OH modifier) to afford the title compound. MS: 392/394 (M + 1). 1H NMR (600 MHz, dmso) delta 8.78 (s, 1H), 8.21 (d, J= 2.2, 1H), 8.04 (dd, J= 2.3, 8.9, 1H), 7.82 (d, J= 8.9, 1H), 5.26 - 5.17 (m, 1H), 3.57 - 3.51 (m, 4H), 2.46 - 2.42 (m, 4H), 2.30 - 2.22 (m, 1H), 2.21 - 2.13 (m, 2H), 1.92 - 1.83 (m, 2H), 1.62 - 1.50 (m, 2H), 1.46 - 1.33 (m, 2H).
  • 5
  • [ 38267-96-8 ]
  • [ 102877-78-1 ]
  • 6-bromo-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% In isopropyl alcohol; at 80℃;Inert atmosphere; To a solution consisting of 6-bromo-4-chloroquinazoline (0.448 g, 1.84 mmol) in 2- propanol (10 mL) was added <strong>[102877-78-1]4-(pyridine-4-yloxy)aniline</strong> (0.360 g, 1.93 mmol). The reaction mixture was heated (80 C) and stirred overnight under a flow of N2. The reaction mixture was cooled to room temperature and then the reaction mixture was filtered over a fritted funnel. The filtered solid was rinsed with excess 2-propanol and dried under high vacuum to afford 6-bromo-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (3F) as an off-white solid (313 mg, 43% yield,97% purity). MS (ESI + m/z 394.0, ESI - m/z 392.0). Next a solution consisting of 6-bromo-N- (4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (0.306 g, 0.77 mmol) in anhydrous ethanol (10 mL) was placed in a 20 mL microwave reaction vial containing a stir bar. Next, 3- aminopyridine-5- boronic acid pinacol ester (6, 0.176 g, 0.80 mmol) was added followed bySiliCatDPP-Pd (5 mol %, 0.26mmol/g loading, 0.150 g) and 10% aqueous potassium carbonate solution (2 equivalents, 1.15 mL, 1.6 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 125 C for one horn in a Biotage Emrys Optimizer microwave. The reaction mixture was allowed to cool to room temperature and then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanoland the filtrate was concentrated under reduced pressure to afford the crude product.Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded 7F 6-(5-aminopyridin-3-yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (50 mg, 15% yield,92% purity) as an off-white solid. MS (ESI + m/z 407.1, ESI m/z 405.1). To a roomtemperature solution of 6-(5 -aminopyridin-3 -yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4- amine (50 mg, 0.12 mmol) in pyridine (3 mL) was added methanesulfonyl chloride (56 mg, 0.5 mmol). The reaction mixture turned dark red which persisted and was stirred for 15 minutes. The reaction mixture was poured into a saturated solution of sodium bicarbonate and the organic material was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The cmde solid was dissolved in methanol and ?dry loaded? on to a silica column eluted with a gradient of 1/9 to 3/7methanol/ethyl acetate to give N-(5-(4-((4-(pyridin-4-yloxy)phenyl)amino)quinazolin-6- yl)pyridin-3-yl)methanesulfonamide (5F, MOL-166, 20 mg, 33% yield, 96% purity) as a solid. ?H NMR (400MHz, DMSO-d6) oe 10.07 (s, 1H), 8.91 (s, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.62 (s, 1H), 8.4-8.5 (m, 3H), 8.15 (dd,J=1.7, 8.6 Hz, 1H), 7.85-8.0(m, 4H), 7.24 (d,J8.9Hz, 2H),6.94 (d, J=4.7 Hz, 2H), 3.08 (s, 3H); MS: (ESI + m/z 485.1, ESI- m/z 483.0).
 

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Technical Information

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