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Structure of 1246765-38-7

Chemical Structure| 1246765-38-7

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Product Details of [ 1246765-38-7 ]

CAS No. :1246765-38-7
Formula : C8H7BrN2O
M.W : 227.06
SMILES Code : O=C1NC2=C(C=C(Br)C=C2)CN1
MDL No. :MFCD13180559
InChI Key :LPMQSNAFKKEZAK-UHFFFAOYSA-N
Pubchem ID :66683712

Safety of [ 1246765-38-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 1246765-38-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 2.0
Molar Refractivity 56.54
TPSA ?

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

41.13 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.65
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

1.19
Log Po/w (WLOGP)?

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

0.98
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.

1.81
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

1.86
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.5

Water Solubility

Log S (ESOL):?

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

-2.37
Solubility 0.974 mg/ml ; 0.00429 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.

-1.65
Solubility 5.09 mg/ml ; 0.0224 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

-3.8
Solubility 0.036 mg/ml ; 0.000158 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

No
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.

-6.84 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

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)

1.95

Application In Synthesis of [ 1246765-38-7 ]

* 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 [ 1246765-38-7 ]

[ 1246765-38-7 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 771583-12-1 ]
  • [ 32315-10-9 ]
  • [ 1246765-38-7 ]
YieldReaction ConditionsOperation in experiment
57.5% Step 2: 6-bromo-3.4-dihvdroquinazolin-2(1 H)-one; To a solution of triphosgene (0.445 g, 1.5 mmol) in tetrahydrofuran (20 mL) was added triethylamine (0.454 g, 4.5 mmol) dropwise at 0 0C under nitrogen. After stirring for 30 min, a solution of 2-(aminomethyl)-4-bromoaniline (0.201 g, 1 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was allowed to stir for 16 h at room temperature. The mixture was diluted with water (15 mL) and the pH of the resultant mixture was adjusted to 8 - 9 by the addition of 1 M aqueous sodium hydroxide. The mixture was extracted three times with ethyl acetate (30 mL). The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by re- crystallization from a mixture o dichloromethane and diethyl ether to give the title compound (0.13 g, 57.5%) as a yellow solid. 1 H NMR (400MHz, DMSO-Cf6) delta ppm 9.12 (s, 1 H), 7.29 (S, 1 H), 7.27(d, J = 8.4 Hz, 1 H), 6.87 (s, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.28 (s, 2H).
55% With triethylamine; at 0 - 20℃; for 16.0h; 10048] To accomplish the synthesis of the desired compounds 6a-f, synthesis of the key intermediate (10) was required, which in turn was envision from the l3uchwald- Hartwig coupling reaction of 6-bromo-3,4-dihydroquinazo- lin-2(1H)-one (9) (H. Venkatesan, F. M. Hocutt, T. K. Jones, M. H. Rabinowitz, I Org. Chem., 75, 3488 (2010)-incor- porated herein by reference in its entirety) with tert-butyl piperazine-1 -carboxylate. Thus the synthesis of compound (9) was commenced with the reduction of bromobenzonitrile with borane to afford diamine (8), which was reacted with triphosgene to get the desired bromide (9) in 23% overall yield from (7). However, the l3uchwald-Hartwig coupling of bromides 9 with tert-butyl piperazine- 1 -carboxylate, under different reaction conditions (PdCl2dppf, KOAc, DMF, 80 C.; Pd(PPh3)4, toluene, ethanol, Na2CO3, reflux) were not successful; the desired 10 was not observed in any case (scheme 1).
  • 3
  • [ 1246765-38-7 ]
  • C17H24N2O [ No CAS ]
  • 6-(4-(4-(4-cyclopropylphenyl)piperazin-1-yl)-3-oxobutyl)-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
  • (R,E)-6-(4-(4-(4-cyclopropylphenyl)piperazin-1-yl)-3-hydroxybut-1-en-1-yl)-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
10.9%; 6.7% With dichlorobis(tri-O-tolylphosphine)palladium; potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;Inert atmosphere; General procedure: 10148] A mixture of bromo derivative 5 (1.6 mmol), potassium carbonate (4.9 mmol) and olefin intermediate 3 (1.6 mmol) in anhydrous DMF (50 mE) was degassed and filled with argon gas. Palladium catalyst (0.08 mmol) was added to the mixture and heated at 1000 C. for 16 h. The resulting pale brown mixture was cooled to room temperature, which was diluted with brine and ethyl acetate followed by filtration to eliminate the insoluble material. A second method to process the reaction mixture was to filter through a pad of celite, and later mix with ethyl acetate and brine for extraction of products. The extracted organic layer was washed with brine, dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash column chromatography on silica gel (230-400 mesh; 40 g) using a gradient solvent mixture of dichloromethane:methanol (100:0 to 95:5). In case of more polar compounds about 0.05% ammonia solution was used as another co-solvent to accelerate the elution. The less polar keto compound 6 was eluted first (Yield=5-20%) followed by olefin product 7 (Yield=5-60%). (rac-)(E)-6-(3-hydroxy-4-(4-(4-propylphenyl)piperazin-1-yl)but-1-en-1-yl)quinolin-2(1H)-one (10) Yield: 0.22 g (33.6%). 1H NMR (400 MHz, DMSO-d6): delta 11.76 (s, 1H), 7.86 (d, 1H), 7.66 (s, 1H), 7.64 (d, 1H), 7.26 (d, 1H), 7.02 (d, 2H), 6.84 (d, 2H), 6.62 (d, 1H), 6.49 (d, 1H), 6.32 (dd, 1H), 4.84 (s, 1H), 4.38 (br. s, 1H), 3.08 (br. s, 4H), 2.61 (br. s, 4H), 2.42 (t, 2H), 1.51 (m, 2H), 0.87 (t, 3H). ES-MS m/z 418.2 (C26H31N3O2+1)+. HPLC data: purity 99.9%, retention time 8.1 min.
  • 4
  • [ 4403-69-4 ]
  • [ 1246765-38-7 ]
  • 5
  • [ 66655-67-2 ]
  • [ 1246765-38-7 ]
YieldReaction ConditionsOperation in experiment
50% With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 2.0h; A solution of N-bromosuccinimide(2.26 g, 12.7 mmol) in 30 ml dry DMF was added drop wise to a solution of 10b (1.79 g,12.1 mmol) in 35 ml dry DMF at 0 C. The mixture was stirred at 0 C for 2 h. Waterwas added and the solution was extracted with ethyl acetate. The organic layer waswashed with brine, and then dried over anhydrous MgSO4. The resulting yellow solidwas purified by crystallization from acetone to afford 10a (1.37 g, 6.00 mmol, 50 %) aswhite solid. 1H-NMR (500 MHz, DMSO-d6): delta = 4.29 (s, 2H), 6.71 (d, 3J = 8.2 Hz, 1H),6.87 (s, 1H), 7.27 (dd, 3J = 8.4 Hz, 4J = 2.3 Hz, 1H), 7.29 (s, 1H), 9.13 (s, 1H). 13C-NMR(125 MHz, DMSO-d6): delta = 41.9, 112.0, 115.3, 120.7, 128.2, 130.1, 137.5, 154.1.
  • 6
  • [ 1246765-38-7 ]
  • [ 192182-56-2 ]
  • 6-(isoquinolin-4-yl)-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux; General procedure: Heteroarylboronic acid (1.3 equivalents), aryl bromide (1 equivalent), and tetrakis(triphenylphosphine) palladium(0) (5mol %) were suspended in DME to give a 0.07-0.1M solution of boronic acid under nitrogen atmosphere. A 0.5M aqueous solution of sodium carbonate (6 equivalents) was added. The mixture was refluxed for 3.5-14h, cooled to room temperature, diluted with water and extracted several times with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, concentrated and purified by flash chromatography and were if necessary recrystallized.
  • 7
  • [ 1246765-38-7 ]
  • [ 1692-25-7 ]
  • 6-(pyridin-3-yl)-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux; General procedure: Heteroarylboronic acid (1.3 equivalents), aryl bromide (1 equivalent), and tetrakis(triphenylphosphine) palladium(0) (5mol %) were suspended in DME to give a 0.07-0.1M solution of boronic acid under nitrogen atmosphere. A 0.5M aqueous solution of sodium carbonate (6 equivalents) was added. The mixture was refluxed for 3.5-14h, cooled to room temperature, diluted with water and extracted several times with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, concentrated and purified by flash chromatography and were if necessary recrystallized.
 

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