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Chemical Structure| 116419-94-4

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Product Details of [ 116419-94-4 ]

CAS No. :116419-94-4
Formula : C10H9F3O2
M.W : 218.17
SMILES Code : O=C(OC)C1=CC=C(C)C(C(F)(F)F)=C1
MDL No. :MFCD14698074
InChI Key :LXUTXZRWQVCTTR-UHFFFAOYSA-N
Pubchem ID :11952921

Safety of [ 116419-94-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 116419-94-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 6
Fraction Csp3 0.3
Num. rotatable bonds 3
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 47.69
TPSA ?

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

26.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.43
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

3.02
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.

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

3.23
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.18

Water Solubility

Log S (ESOL):?

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

-3.19
Solubility 0.14 mg/ml ; 0.000641 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.

-3.24
Solubility 0.126 mg/ml ; 0.000579 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

-3.75
Solubility 0.0384 mg/ml ; 0.000176 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.

-5.49 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)

1.78

Application In Synthesis of [ 116419-94-4 ]

* 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 [ 116419-94-4 ]
  • Downstream synthetic route of [ 116419-94-4 ]

[ 116419-94-4 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 74-88-4 ]
  • [ 116419-94-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With potassium hydroxide In dimethyl sulfoxide at 25℃; for 0.75 h;
Stage #2: at 25℃; for 2 h;
A solution of KOH (84 tug, 1.5 mmol) in DMSO (5 ml) was stilled fot- 30 min at 25 0C. The above slurry was then treated with 4-methyl-3-trifluoromethyl-benzoic acid (306 mg, 1.5 mmol) in H)MSO (5 ml) and the resulting mixture was stirred for 15 min, and iodottiethane (426 mg, 3 mmol) was then added to the mixture. The reaction was stirred for 2 h at 25 °C and then quenched with water. The resulting solution was extracted with βtOAc. The organic layer was washed with NaCl(sat) and dried with lsfa2Sψ4(S). The organics were removed under reduced pressure to give the title compound as an oil 327 mg (100percent). NMR: 8.10 (m, 214), 7.60 (s, IH), 3.86 (s, 3H), 2.45 (s, 3H); tn/z 218.
100%
Stage #1: With potassium hydroxide In dimethyl sulfoxide at 25℃; for 0.75 h;
Stage #2: at 25℃; for 2 h;
Method 22; 4-Methyl-3-trifluoromethyl-benzoic acid methyl ester; A solution of KOH (84 mg, 1.5 mmol) in DMSO (5 ml) was stirred for 30 min at25 °C. The above slurry was treated with 4-methyl-3-trifluoromethyl-benzoic acid (306 mg, 1.5 mmol) in DMSO (5 ml) and the resulting mixture was stirred for 15 min, and iodomethane (426 mg, 3 mmol) was added to the mixture. The reaction was stirred for 2 h at 25 °C and then quenched with water. The resulting solution was extracted with EtOAc. The organic layer was washed with NaCl(sat) and dried with Na2SO4(S). The organics were removed under reduced pressure to give the title compound as an oil 327 mg (100percent). NMR: 8.10 (m, 2H), 7.60 (s, IH), 3.86 (s, 3H), 2.45 (s, 3H); m/z 218
100%
Stage #1: With potassium hydroxide In dimethyl sulfoxide for 0.25 h;
Stage #2: at 0 - 25℃; for 2 h;
Method 57; 4-Methyl-3-trifluoromethyl-benzoic acid methyl ester; A slurry of potassium hydroxide (84 mg, 1.5 mmol) in DMSO was treated with a solution of 4-methyl-3-trifluoromethyl-benzoic acid (306 mg, 1.5 mmol) in DMSO (5 ml). The resulting mixture was stirred for 15 min and cooled with an ice bath. After the addition of methyl iodide (426 mg, 3 mmol), the mixture was stirred for 2 h at 25 °C. The reaction mixture was quenched with water and extracted with EtOAc. The organics were washed with NaCl(sat), dried with Na2SO4(s) and concentrated under reduced pressure to give 327 mg (100percent). NMR: 8.10 (m, 2H), 7.60 (s, IH), 3.86 (s, 3H), 2.45 (s, 3H); m/z 218
References: [1] Patent: WO2006/67446, 2006, A1, . Location in patent: Page/Page column 130.
[2] Patent: WO2006/79791, 2006, A1, . Location in patent: Page/Page column 39.
[3] Patent: WO2007/71963, 2007, A2, . Location in patent: Page/Page column 56.
  • 2
  • [ 261952-01-6 ]
  • [ 74-88-4 ]
  • [ 116419-94-4 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In acetone at 20℃; for 24 h; To a mixture of 4-methyl-3-(trifluoromethyl) benzoic acid (1 equiv), K2C03 (1.5 equiv) in acetone (15 times) was added Mel (1.5 equiv) at room temperature. Stirring was continued for 24h. Reaction was monitored by thin layer chromatography. The salts were filtered and resulting filtrate was concentrated, diluted with water, extracted with ethyl acetate. Concentration of organic layer afforded the pale yellow oil (95percent yield). ESI MS m/z -219 (M+H l)+.
References: [1] Patent: WO2015/186137, 2015, A1, . Location in patent: Page/Page column 24.
[2] Patent: US2016/235734, 2016, A1, . Location in patent: Paragraph 0504; 0505.
[3] Patent: US2018/16267, 2018, A1, . Location in patent: Paragraph 0222.
  • 3
  • [ 261952-01-6 ]
  • [ 67-56-1 ]
  • [ 116419-94-4 ]
YieldReaction ConditionsOperation in experiment
96% Reflux 20 mmol of 3-trifluoromethyl-4-methyl-benzoic acid was dissolved in a round-bottomed flask containing 60 mL of methanol.A catalytic amount (3percent mmol) of concentrated sulfuric acid was added and the reaction was stirred at reflux overnight.The solvent was removed on a rotary evaporator, and 30 ml of a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate (2×50 ml) and drying over anhydrous sodium sulfate.The solvent was removed on a rotary evaporator to give 3-trifluoromethyl-4-methyl-benzoic acid methyl ester compound a (yield: 96percent).
95% for 6 h; Reflux Example 88: preparation of methyl 5-(5-(4~((3-(dimethylamino)pyrrolidin~1-yl)methyl)-3- (trifluoro-methyl)benzamido)-2-methylbenzamido)-1H~pyrrolof2,3-b]pyridine-2- carboxylate (ND0119); Step 1: preparation of methyl 3-(trifluoromethyl)-4-methylbenzoate; A reactor is charged with 1q (4.9mmol) of 3-(trifluoromethylH-methylbenzoic acid in 10ml methanol in the presence of a catalytic amount of sulphuric acid. The mixture is heated for 6 hours at reflux. The solvent is then evaporated under reduced pressure and 100ml of a saturated sodium bicarbonate solution is added to the mixture. The solution is extracted by 3*30ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure to give the expected product (1α. 95percent).
95% Reflux General procedure: General procedure for esterification: 4-methyl-3 -substituted benzoic acid (24 mmol) in methanol (50 mL) with H2SO4 (0.260 mL, 4.8 mmol) are stirred and heated to reflux for one night. Methanol is evaporated and product is extracted at pH = 7 with EtOAc.
88.4%
Stage #1: at 0 - 20℃; for 1 h;
Stage #2: at 80℃; for 5 h;
To a stirred methanol (300 mL) was added dropwisely sulfurous dichloride (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. To this stirred solution was added 4-methyl-3-(trifluoromethyl)benzoic acid (30 g, 0.15 mol) in one portion at room temperature. The mixture was stirred at 80 °C for 5 hrs. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate anhydrous and concentrated. The residue (28.3 g, yield: 88.4percent) was used into next step directly. 1H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 3.90 (s, 3H), 2.50 (s, 3H)ppm.
84.8% for 24 h; Reflux 4-methyl-3-(trifluoromethyl) benzoic acid (2.04 g, 10 mmol, 1.0 eq) in 25 mL of MeOH was added 2 mL of concentrated sulfuric acid. And the reaction monitored by TLC was completed after 24 hours under reflux with stirring. MeOH was distilled off and DCM was added to dissolved the residue. The solution was washed successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and water. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the product (1.85 g, 84.8percent yield) for the next step.

References: [1] Patent: CN104844566, 2018, B, . Location in patent: Paragraph 0101; 0107; 0108.
[2] Patent: WO2010/92489, 2010, A1, . Location in patent: Page/Page column 96-97.
[3] Patent: WO2014/102378, 2014, A1, . Location in patent: Page/Page column 48-49.
[4] Patent: WO2014/206344, 2014, A1, . Location in patent: Page/Page column 63.
[5] Patent: US2017/305920, 2017, A1, . Location in patent: Paragraph 0170; 0171.
[6] Patent: US2011/281893, 2011, A1, . Location in patent: Page/Page column 9.
[7] Patent: CN106188005, 2016, A, . Location in patent: Paragraph 0084.
  • 4
  • [ 99-75-2 ]
  • [ 76-05-1 ]
  • [ 116419-94-4 ]
References: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41.
  • 5
  • [ 104-85-8 ]
  • [ 116419-94-4 ]
References: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41.
  • 6
  • [ 186581-53-3 ]
  • [ 261952-01-6 ]
  • [ 116419-94-4 ]
References: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41.
 

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