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Chemical Structure| 881402-22-8

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Product Details of [ 881402-22-8 ]

CAS No. :881402-22-8
Formula : C7H5BF4O3
M.W : 223.92
SMILES Code : FC(F)(F)OC1=CC=C(F)C(B(O)O)=C1
MDL No. :MFCD09027234
InChI Key :NGTLLTDDJHXHQE-UHFFFAOYSA-N
Pubchem ID :44717610

Safety of [ 881402-22-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 881402-22-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 3
Num. H-bond acceptors 7.0
Num. H-bond donors 2.0
Molar Refractivity 42.91
TPSA ?

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

49.69 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

2.11
Log Po/w (WLOGP)?

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

2.08
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.

0.92
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

0.34
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.09

Water Solubility

Log S (ESOL):?

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

-2.66
Solubility 0.495 mg/ml ; 0.00221 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.

-2.78
Solubility 0.368 mg/ml ; 0.00164 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

-2.2
Solubility 1.41 mg/ml ; 0.00628 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.

-6.17 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<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)

2.38

Application In Synthesis of [ 881402-22-8 ]

* 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 [ 881402-22-8 ]

[ 881402-22-8 ] Synthesis Path-Downstream   1~12

  • 1
  • C9H9BF4O3 [ No CAS ]
  • [ 881402-22-8 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; water; In diethyl ether; Boron trifluoride etherate (0.453 ml, 3.89 mmol) and trimethyl borate (0.867 ml, 7.77 mmol) were stirred in anhydrous tetrahydrofuran (THF, 10 ml) for 10 minutes to form dimethoxyfluoroborane in situ.To a solution of the 4-fluoro(trifluoromethoxy)benzene (2.0 g, 11.1 mmol) in dry THF (30 ml) at -780C, was added ethylenediaminetetraacetic acid (EDTA, 1.36 g, 11.7 mmol) followed by a 1.4 M solution of sec-butyllithium in cyclohexane (8.33 ml, 11.7 mmol) and the reaction stirred for 2 hours under nitrogen. To this reaction mixture at - 780C, was then added dropwise the preformed dimethoxyfluoroborane mixture. The reaction was stirred at -780C for 30 minutes, warmed to room temperature for 30 minutes, and then quenched with water (10 ml). The volume of the reaction mixture was reduced in vacuo, then the residue dissolved in diethyl ether (10 ml) and washed with an aqueous solution of 10percent NaOH (50 ml). The aqueous layer was acidified and extracted with ethyl acetate (3 x 40 ml). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a single regioisomer (1.51 g).LCMS Rt = 1.38 minMS m/z 223 [M]-
  • 2
  • [ 881402-22-8 ]
  • [ 1176954-98-5 ]
  • [ 1176064-06-4 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 160℃; for 0.166667h;Microwave irradiation; l-[(6-Chloro-3-pyridinyl)methyl]-2-hydroxy-3-iodo-4-oxo-4H-pyrido[l,2- alphajpyrimidinium inner salt (i.e. the product of Step C) (206 mg, 0.5 mmol), 2-fluoro-5- (trifluoromethoxy)benzeneboronic acid (224 mg, 1 mmol) and bis(triphenylphosphino)- palladium dichloride (35 mg, 0.005 mmol) were dissolved in dioxane (2 mL). Aqueous sodium carbonate solution (2 N, 1 mL) was added, and the reaction mixture was heated in a microwave reactor for 10 min at 160 0C. The cooled reaction mixture was poured directly onto a silica gel column and eluted successively with hexanes, 30percent ethyl acetate in hexanes, 50percent ethyl acetate in hexanes, and finally ethyl acetate to yield the title compound (compound number 58), a compound of this invention, as a solid (20 mg). 1H NMR (CDCl3) 5 9.53 (d, IH), 8.49 (s, IH), 8.11 (dd, IH), 7.69 (d, IH), 7.50 (d, IH), 7.41 (m, 2H), 7.34 (d, IH), 7.16 (d, 2H), 7.58 (br s, 2H).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 160℃; for 0.166667h;Microwave irradiation; Step D: Preparation of l-[(6-chloro-3-pyridinyl)methyl]-3-[2-fluoro-5-(trifluoromethoxy)phenyl]-2-hydroxy-4-oxo-4H-pyrido[l,2-alpha]pyrimidinium inner saltl-[(6-Chloro-3-pyridinyl)methyl]-2-hydroxy-3-iodo-4-oxo-4H-pyrido[l,2- alpha]pyrimidinium inner salt (i.e. the product of Step C) (206 mg, 0.5 mmol), 2-fluoro-5- (trifluoromethoxy)benzeneboronic acid (224 mg, 1 mmol) and dichlorobis(triphenyl- phosphine)palladium(II) (35 mg, 0.005 mmol) were dissolved in dioxane (2 mL). Aqueous sodium carbonate solution (2 N, 1 mL) was added, and the reaction mixture was heated in a microwave reactor for 10 min at 160 0C. The cooled reaction mixture was poured directly onto a silica gel column and eluted successively with hexanes, 30percent ethyl acetate in hexanes, 50percent ethyl acetate in hexanes, and finally ethyl acetate to yield the title compound as a solid (20 mg).1H NMR (CDCl3) delta 9.53 (d, IH), 8.49 (s, IH), 8.11 (dd, IH), 7.69 (d, IH), 7.50 (d, IH), 7.41 (m, 2H), 7.34 (d, IH), 7.16 (d, 2H), 7.58 (br s, 2H).
  • 3
  • [ 881402-22-8 ]
  • 2,4-dichloro-5-(prop-1-en-2-yl)pyridine [ No CAS ]
  • 4-chloro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-isopropenylpyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
250 mg With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 3.0h;Inert atmosphere; A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (800 mg, 4.26 mmol [4-fluoro-3-(trifluoromethoxy)phenyl]boronic acid (606 mg, 3.1 mmol) and sodium carbonate (1.3 g, 12.8 mmol) in a mixture of DME (5 mL) and water (2.5 mL) and degassed with nitrogen for 15 min. Then Pd(PPh3)2.Cl2 (147 mg, 0.21 mmol) and again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100 C for 3h. The reaction was monitored by LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (25 mL) and extracted with EtOAc (2x50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified by chromatography to obtain 4-chloro-2-[2-fluoro-5- (trifluoromethoxy)phenyl]-5-isopropenyl-pyridine (250 mg) as an oil.
  • 4
  • [ 881402-22-8 ]
  • C13H13ClO3 [ No CAS ]
  • C20H16F4O4 [ No CAS ]
  • 5
  • [ 881402-22-8 ]
  • C14H15BrO3 [ No CAS ]
  • methyl 2-((R)-6-(2-fluoro-5-(trifluoromethoxy)phenyl)chroman-2-yl)cyclopropanecarboxylate [ No CAS ]
  • 6
  • [ 881402-22-8 ]
  • C21H20F4O5 [ No CAS ]
  • 7
  • [ 881402-22-8 ]
  • 2-fluoro-5-(trifluoromethoxy)phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dihydrogen peroxide; In ethanol; at 0 - 5℃; for 3.0h; To a stirred soln. of(2-fluoro-5-(trifiuoro- methoxy)phenvi)boronic acid (1340 g, 60 mmoi) in anhyd. EtOH (20 mL) was added dropise 30percent H202 (10.2 inL, 90 minol) at 0-5 °C, and the reaction mixture was stirred for 3 h. The reaction was quenched with a satd, soin. of Na2S2O3, and concentrated in vueno. The resulting residue was dissolved in DCM (30 mL), and the soin. was washed with brine (10 mLx2). Theorganic layer was concentrated in vacu.o to give the title compound.
  • 8
  • [ 881402-22-8 ]
  • 1-fluoro-2-methoxy-4-(trifluoromethoxy)benzene [ No CAS ]
  • 9
  • [ 881402-22-8 ]
  • 1-bromo-2-fluoro-3-methoxy-5-(trifluoromethoxy)benzene [ No CAS ]
  • 10
  • [ 881402-22-8 ]
  • (R)-methyl 3-(6-bromochroman-2-yl)propanoate [ No CAS ]
  • C20H18F4O4 [ No CAS ]
  • 11
  • [ 881402-22-8 ]
  • (S)-methyl 3-(6-bromochroman-2-yl)propanoate [ No CAS ]
  • C20H18F4O4 [ No CAS ]
  • 12
  • [ 40971-95-7 ]
  • [ 881402-22-8 ]
  • C13H5F7N4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
22.78 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16.0h;Inert atmosphere; A mixture of A-1 (150.00 mg, 673.98 mmol), <strong>[881402-22-8][2-fluoro-5-(trifluoromethoxy)phenyl]boronic acid</strong> (150.92 mg, 673.98 mmol) and Cs2C03 (439.19 mg, 1.35 mmol) in dioxane (3 mL) and H20 (300 __) was added Pd(dppf)Cl2.CH2Ci2 (82.56 mg, 101.10 mmol) was stirred at 90 C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated to give a residue that was purified by prep-TLC (silica gel, EtOAc:PE = 1:2) to afford Compound 18 (22.78 mg, 62.21 mmol) as a solid. 1H NMR (400MHz, CDC13) _ = 8.34 (d, 1H), 7.85 - 7.79 (m, 2H), 7.50 - 7.43 (m, 1H), 7.37 - 7.31 (t, 1H). LCMS R, = 1.19 min using Method A, MS ESI calcd. for C13H6F7N40 [M+H]+ 367.0, found 367.2.
 

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