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Product Details of [ 740081-22-5 ]

CAS No. :740081-22-5
Formula : C17H13ClFN3O3
M.W : 361.75
SMILES Code : CC(OC1=CC2=C(NC3=CC=CC(Cl)=C3F)N=CN=C2C=C1OC)=O
MDL No. :MFCD26395271
InChI Key :YJNQYSVKLRFVQN-UHFFFAOYSA-N
Pubchem ID :57476867

Safety of [ 740081-22-5 ]

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

Computational Chemistry of [ 740081-22-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 25
Num. arom. heavy atoms 16
Fraction Csp3 0.12
Num. rotatable bonds 5
Num. H-bond acceptors 6.0
Num. H-bond donors 1.0
Molar Refractivity 92.04
TPSA ?

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

73.34 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.33
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

3.87
Log Po/w (WLOGP)?

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

4.52
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.

3.25
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

3.67
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.73

Water Solubility

Log S (ESOL):?

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

-4.66
Solubility 0.00783 mg/ml ; 0.0000216 mol/l
Class?

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

Moderately soluble
Log S (Ali)?

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

-5.11
Solubility 0.00283 mg/ml ; 0.00000781 mol/l
Class?

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

Moderately 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

-6.95
Solubility 0.0000407 mg/ml ; 0.000000112 mol/l
Class?

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

Poorly 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

No
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

Yes
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

Yes
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

Yes
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.

-5.76 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

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<2.0
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)

2.77

Application In Synthesis of [ 740081-22-5 ]

* 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 [ 740081-22-5 ]

[ 740081-22-5 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 740081-22-5 ]
  • [ 612501-52-7 ]
YieldReaction ConditionsOperation in experiment
100% With ammonia methyl alcohol; In methanol; at 20℃; for 2h; Taking compound 3 (200 mg) dissolved in methanol (2 ml) in, adding methanol and ammonia solution (7 N, 1 ml), then stirred at room temperature 2 hours; the reaction the fluid turns on lathe job to the compound 1 (white powder, 176 mg, quant.).
83% With ammonia; N,N-diethylaniline; In methanol; at 20℃; for 18h; To a stirred solution of compound 6 (2.30 g, 5.79 mmol) in MeOH (50 mL) was added concentrated ammonia (4.0 mL). The reaction mixture was stirred at rt for 18 h. The resultant precipitate was filtered, and washed with MeOH to afford 7 (1.54 g, 83%) as a pale yellow solid, mp 280-282 C. 1H NMR (DMSO-d6): d 9.75 (s, 1H), 9.48 (s, 1H), 8.35 (s, 1H), 7.66 (s, 1H), 7.52 (t, J = 6.5 Hz, 1H), 7.45 (t,J = 7.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.21 (s, 1H), 3.98 (s, 3H).
81% With ammonia; In methanol; for 2h;Sealed tube; Inert atmosphere; Heating; To JGK018 (550 mg, 1.520 mmol) was dropwise added ammonia solution (8.0 mL, 7 N in methanol). After being heated at 50 C (bath temperature) in sealed tube with stirring for 2 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting white solid were washed successively with Et20 (2 x 50 mL) and collected to give 13 (394 mg, 81%); The resulting spectroscopic data was matched with that of Zhang, X. et al. Med. Chem. 2015, 58, 8200-8215.
77% With ammonia; In methanol; water; at 50℃; for 2h; 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE HYDROCHLORIDE FROM step 1 (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ml) was added, and the solution heated to 50C with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3x 200 ml), and dried in vacuo at 60C over diphosphorous pentoxide, giving the product as an off white solid (5.40 g, 77%); H NMR : 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br. s, 1H) ; Mass Spectrum: 320.4, 322.4.
77% With ammonia; In water; at 50℃; for 2h; 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE hydrochloride from step 1 (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ml) was added, and the solution heated to 50C with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3x 200 ml), and dried in vacuo at 60C over diphosphorous pentoxide, giving the product as an off white solid (5.40 g, 77%). 1H NMR : 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br. s, 1H); Mass Spectrum : 320.4, 322.4.
With methanol; potassium carbonate; at 20℃; Intermediate 74-[(3-Chloro- -fluorophenyl)aminol-7-methoxyquinazolin-6-olTo a solution of Intermediate 6 (181 g, 0.396 mol) in MeOH (2 L) was added potassium carbonate (138 g, 1 mol) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the solid washed with MeOH. The filtrate was concentrated in vacuo to afford Intermediate 7 (280 g, 60% purity, contained potassium carbonate). 1H NMR (DMSO-d6400MHz): delta 8.01 (s, 1H), 7.61-7.58 (m, 1H), 7.27-7.24 (m, 1H), 7.17-7.13 (m, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 3.79 (s, 3H).
With potassium carbonate; In methanol; at 20℃; To a solution of Intermediate 6 (181 g, 0.396 mol) in MeOH (2 L) was added potassium carbonate (138 g, 1 mol) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the solid washed with MeOH. The filtrate was concentrated in vacuo to afford Intermediate 7 (280 g, 60% purity, contained potassium carbonate). 1H NMR (DMSO-d6 400 MHz): delta 8.01 (s, 1H), 7.61-7.58 (m, 1H), 7.27-7.24 (m, 1H), 7.17-7.13 (m, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 3.79 (s, 3H).
30 g With methanol; ammonium hydroxide; at 20 - 30℃; for 6h; 35g of compound 4,100g ammonia water,70g of methanol was added to the reaction flask,At a reaction temperature of 20-30 C,Stir for 6h,After TLC detection reaction is complete, suction filtration, and then dried at 40 ~ 50 C, to obtain 30g of compound 5;

 

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