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Structure of 183438-24-6

Chemical Structure| 183438-24-6

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Product Details of [ 183438-24-6 ]

CAS No. :183438-24-6
Formula : C4H2BrIN2
M.W : 284.88
SMILES Code : BrC1=CN=C(N=C1)I
MDL No. :MFCD01318111
InChI Key :ZEZKXPQIDURFKA-UHFFFAOYSA-N
Pubchem ID :7006651

Safety of [ 183438-24-6 ]

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

Computational Chemistry of [ 183438-24-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 42.45
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.

1.92
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

1.58
Log Po/w (WLOGP)?

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

1.84
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.

1.33
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

2.71
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.88

Water Solubility

Log S (ESOL):?

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

-3.16
Solubility 0.199 mg/ml ; 0.000697 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.

-1.73
Solubility 5.28 mg/ml ; 0.0185 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

-3.45
Solubility 0.101 mg/ml ; 0.000355 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.

-6.92 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<0.0
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)

2.03

Application In Synthesis of [ 183438-24-6 ]

* 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.

  • Upstream synthesis route of [ 183438-24-6 ]
  • Downstream synthetic route of [ 183438-24-6 ]

[ 183438-24-6 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 183438-24-6 ]
  • [ 108-95-2 ]
  • [ 257280-25-4 ]
YieldReaction ConditionsOperation in experiment
92% at 165℃; for 4 h; Inert atmosphere Step A:
Preparation of 5-bromo-2-phenoxypyrimidine
A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 1.01 g, 3.57 mmol), phenol (Aldrich, 3.35 g, 35.7 mmol), and potassium carbonate (Aldrich, 4.93 g, 35.7 mmol) was stirred neat at 165° C. under a nitrogen atmosphere for four hours.
After cooling to room temperature, the mixture was partitioned between ethyl acetate (250 mL) and 1 N hydrochloric acid (4*200 mL).
The organic layer was washed with 1 N hydrochloric acid until disappearance of color in the aqueous layer.
The phases were separated and the organic phase was washed with water (100 mL) and brine (100 mL).
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide an orange oil (1.1 g).
The product was purified by flash silica column chromatography.
Elution through an 80-g Silicycle.(R). flash silica cartridge with 10percent ethyl acetate in hexanes afforded the title compound as a white solid (0.82 g, 92percent yield); Rf 0.51 with 8:2 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 8.56 (s, 2H), 7.46-7.41 (m, 2H), 7.30-7.24 (m, 1H), 7.20-7.16 (m, 2H); MS (APCI+) m/z 252.9 (M+1).
87% With 2-Picolinic acid; potassium phosphate; copper(l) iodide In dimethyl sulfoxide at 100℃; for 20 h; Inert atmosphere Procedure: 5-bromo-2-iodopyrimidine (3 mmol), phenol (3.2 mmol), 2-picolinic acid (0.3 mmol), cuprous iodide CuI (0.3 mmol), potassium phosphate (4.5 mmol) was placed in 25 mL dry In a flask, 15 mL of DMSO was added and the mixture was heated to 100° C. under Ar protection. After about 20 hours of reaction, TLC conversion was complete. After the mixture was cooled to room temperature, a large amount of ethyl acetate was added, washed with water four times and extracted twice with ethyl acetate. The EA phases were combined and washed with saturated brine. The organic phase was dried, filtered, evaporated to dryness and purified by silica gel column chromatography to give 1.1 g of a white product. , Yield 87percent
References: [1] Patent: US2010/75990, 2010, A1, . Location in patent: Page/Page column 40.
[2] Patent: CN108069974, 2018, A, . Location in patent: Paragraph 0194-0196.
  • 2
  • [ 97674-02-7 ]
  • [ 183438-24-6 ]
  • [ 1189169-37-6 ]
YieldReaction ConditionsOperation in experiment
70% With bis-triphenylphosphine-palladium(II) chloride In toluene at 130℃; for 18 h; Inert atmosphere 5-bromo-2-iodopyrimidine (16 g, 56.16 mmol) and tributyl(l- ethoxyethenyl)stannane (25 g, 69.22 mmol) were dissolved in toluene (500 mL) and purged with N2for 10 mins. Palladium (2+) chloride - triphenylphosphane (1 :2:2) (3.5 g, 4.99 mmol) was added and the reaction mixture was heated at 130 °C for 18 h. The reaction was allowed to cool to r.t. Water (70 ml) and 6M HC1 (280 ml) were added and - -the reaction mixture was allowed to stir vigorously for 4 h. The pH of the mixture was adjusted to pH 7 by the addition of saturated aqueous Na2C03(approximately 300 mL) and the mixture extracted with EtOAc (3 x 350 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (Si02, 20-100percent EtOAc in Heptane) to afford the title compound as a golden-yellow solid (7.9 g,70percent). 1H NMR (500 MHz, CDC13) δ 8.97 (s, 2H), 2.77 (s, 3H).
References: [1] Patent: WO2015/86526, 2015, A1, . Location in patent: Page/Page column 153; 154.
 

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