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Chemical Structure| 705-24-8 Chemical Structure| 705-24-8

Structure of 705-24-8

Chemical Structure| 705-24-8

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Product Details of [ 705-24-8 ]

CAS No. :705-24-8
Formula : C5HCl2F3N2
M.W : 216.98
SMILES Code : ClC1=NC(=NC(=C1)Cl)C(F)(F)F
MDL No. :MFCD08436597
InChI Key :QFWVAJQVYBRTCL-UHFFFAOYSA-N
Pubchem ID :15713197

Safety of [ 705-24-8 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301-H314
Precautionary Statements:P280-P301+P310-P305+P351+P338-P310
Class:8(6.1)
UN#:2922
Packing Group:

Computational Chemistry of [ 705-24-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 37.05
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.

1.97
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

3.05
Log Po/w (WLOGP)?

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

3.95
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.

1.92
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

3.3
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.84

Water Solubility

Log S (ESOL):?

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

-3.41
Solubility 0.0843 mg/ml ; 0.000388 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.

-3.26
Solubility 0.12 mg/ml ; 0.000553 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

-3.78
Solubility 0.0362 mg/ml ; 0.000167 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.

-5.46 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)

1.56

Application In Synthesis of [ 705-24-8 ]

* 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 [ 705-24-8 ]

[ 705-24-8 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 705-24-8 ]
  • [ 124-40-3 ]
  • [ 866648-53-5 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20.0℃; for 60.0h; To a suspension of 2-trifluoromethyl-pyrimidine-4, 6-diol (3.25 g) in POC13 (7.89 mL) was added Et3N (5.00 mL). The mixture was stirred at 120C for 3 hr, cooled to ambient temperature, and poured into ice water. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgS04, filtrated, and concentrated under reduced pressure to give 4, 6-dichloro-2-trifluoromethyl-pyrimidine. To the solution of the above material (1.00 g) in THF (10 mL) were added iPrzNEt (0.98 mL) and 50% aqueous Me2NH (0.48 mL). The mixture was stirred at ambient temperature for 60 hr. To the solution was added saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCI3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (silica gel, 5% to 25% EtOAc in hexane) to give (6-chloro-2- trifluoromethyl-pyrimidin-4-yl)-dimethyl-amine (728 mg). ESI MS m/e 225 M+ ; 1H NMR (300 MHz, CDC13) 8 2.77-3. 61 (m, 6 H), 6.50 (s, 1 H).
  • 2
  • [ 672-47-9 ]
  • [ 705-24-8 ]
YieldReaction ConditionsOperation in experiment
78.8% With trichlorophosphate; In water; triethylamine; EXAMPLE 2 4,6-Dichloro-2-trifluoromethylpyrimidine, Compound V, Step 2 4,6-Dihydroxy-2-trifluoromethylpyrimidine (VI; 540 g; 3.0 M) was stirred with phosphorous oxychloride (1300 mL; 2147 g; 14.0 M) in a 5 L round-bottom flask with mechanical stirrer and triethylamine (607 g; 6.0 M) was added over 1 hr. After the exotherm, the reaction was heated on a stem-bath for 3 hr. The reaction mixture was cooled to 40, and then it was poured with stirring into a mixture of 10 kg ice and 2 kg water. The mixture was extracted with 4*0.5 L methylene chloride. The combined extracts were dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give the crude compound V. When further purification was desired, the crude V was distilled at 48-50/2 mm using a steam-bath (Lit. b.p. 38/1 mm) to give a colorless liquid. The purified yield was 78.8%. Anal. Calcd. for C5 HCl2 F3 N2: C, 27.68; H, 0.47; N, 12.91. Found: C, 27.45; H, 0.39; N, 12.86.
With triethylamine; trichlorophosphate; at 120℃; for 3h; To a suspension of 2-trifluoromethyl-pyrimidine-4, 6-diol (3.25 g) in POC13 (7.89 mL) was added Et3N (5.00 mL). The mixture was stirred at 120C for 3 hr, cooled to ambient temperature, and poured into ice water. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgS04, filtrated, and concentrated under reduced pressure to give 4, 6-dichloro-2-trifluoromethyl-pyrimidine. To the solution of the above material (1.00 g) in THF (10 mL) were added iPrzNEt (0.98 mL) and 50% aqueous Me2NH (0.48 mL). The mixture was stirred at ambient temperature for 60 hr. To the solution was added saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCI3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (silica gel, 5% to 25% EtOAc in hexane) to give (6-chloro-2- trifluoromethyl-pyrimidin-4-yl)-dimethyl-amine (728 mg). ESI MS m/e 225 M+ ; 1H NMR (300 MHz, CDC13) 8 2.77-3. 61 (m, 6 H), 6.50 (s, 1 H).
31.4 g With triethylamine; trichlorophosphate; at 5 - 105℃; for 4h; To the reaction flask was added phosphorus oxychloride 144.1 g,Stirring 2-trifluoromethyl-4, 6-dihydroxypyrimidine 36g, stirring,Cooling to 5 ~ 10 C dropping triethylamine 55.4 mL, dropwise warming to 100 ~ 105 C for 4 hours,After the control reaction qualified, the control 0 ~ 5 The reaction solution was added to ice water, after stirring,Then add dichloromethane and stir the layers, add methylene chloride in the aqueous phase to extract, combine the organic phases, wash,Filtration and drying gave the crude product. The crude product was distilled to collect the steamed product, 31.4 g of a colorless liquid,Yield 72.4%, HPLC 99.9%.
  • 3
  • [ 705-24-8 ]
  • [ 50607-30-2 ]
  • 4-((6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)oxy)-5,6-dihydropyridin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% To a solution of 1 -methylpiperidin-4-ol (35 mg, 0.30 mmol) in THF (0.5 mL) at 0°C was added 60percent NaH (12 mg, 0.30 mmol). After the mixture was stirred for 20 minutes, a solution of Intermediate 2 (42 mg, 0.10 mmol) in THF (0.5 mL) was added. Then the ice bath was removed, and the reaction mixture was stirred at room temperature for two hours. The reaction was quenched by water (0.1 mL), and concentrated. The residue was purified directly by MS-HPLC to afford Compound 39 (18 mg, 35percent). LCMS (method A): m/z 503.4 (M+H)+. 'H NMR (CDCI3) delta 8.50 (s, 1H), 77.44 (d, 2H), 7.17 (d, 2H), 5.72 (d, 1H), 5.31 (m, 1H), 4.60 (br, 1H), 3.60 (m, 1H), 3.40 (m, 2H), 3.24 (br, 1H), 3.03 (br, 2H), 2.92-2.77 (m, 4H), 2.40 (br, 1H), 2.25 (m, 3H), 2.1 1-1.88 (m,4H); Following procedure as described in Example 2, and replacing THF with DMF, <strong>[50607-30-2]piperidine-2,4-dione</strong> (249 mg, 2.20 mmol) was converted to Compound 3A. The crude material was purified by silica gel chromatography (0-90percent EA/hexane) to afford Compound 3A (375 mg, 64percent). LCMS (method A): m/z 294.3 (M+H)+. XH NMR (CDC13): delta 7.14 (s, 1H), 5.97 (br s, 1H), 5.83 (s, 1H), 3.60 (t, 2H), 2.72 (m, 2H).
 

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