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Chemical Structure| 67515-59-7

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Product Details of [ 67515-59-7 ]

CAS No. :67515-59-7
Formula : C8H3F4N
M.W : 189.11
SMILES Code : N#CC1=CC=C(F)C(C(F)(F)F)=C1
MDL No. :MFCD00061284
InChI Key :CQZQCORFYSSCFY-UHFFFAOYSA-N
Pubchem ID :144255

Safety of [ 67515-59-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H312-H315-H319-H332-H335
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501

Computational Chemistry of [ 67515-59-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 1
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 36.12
TPSA ?

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

23.79 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.83
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

2.63
Log Po/w (WLOGP)?

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

4.29
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.

2.94
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

3.25
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.99

Water Solubility

Log S (ESOL):?

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

-2.94
Solubility 0.215 mg/ml ; 0.00114 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 0.314 mg/ml ; 0.00166 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

-3.65
Solubility 0.0422 mg/ml ; 0.000223 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.

-5.59 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

2.0
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)

1.93

Application In Synthesis of [ 67515-59-7 ]

* 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 [ 67515-59-7 ]

[ 67515-59-7 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 111-49-9 ]
  • [ 67515-59-7 ]
  • C14H15F3N2 [ No CAS ]
  • 2
  • [ 67515-59-7 ]
  • [ 6760-99-2 ]
  • [ 735331-03-0 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; EXAMPLE 347A 4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzonitrile <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (1.35 g, 7.14 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (1.26 g, 8.57 mmol), and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) were combined in DMSO (15 mL) and heated at 120 C. for 24 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The separated aqueous phase was extracted with diethyl ether and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; Example 347A 4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzonitrile <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (1.35 g, 7.14 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (1.26 g, 8.57 mmol), and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) were combined in DMSO (15 mL) and heated at 120 C. for 24 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The separated aqueous phase was extracted with diethyl ether and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
  • 3
  • [ 67515-59-7 ]
  • 4-fluoro-3-(trifluoromethyl)benzimidamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% A solution of 4-Fluoro-3-trifluoromethyl-benzonitrile (10 g, 52.9 mmol) sodium methoxide (10.6 mL of a 0.5 M solution in methanol, 5.3 mmol; 0.1 eq) in methanol (40 mL) was allowed to stir 12-36 h at room temperature. Acetic acid (0.32 g, 5.3 mmol) was added followed by NH4Cl (2.8 g, 52.9 mmol). The reaction was stirred at 50 C. for 24 h. The reaction was cooled, the unreacted ammonium chloride removed by filtration and the resultant white solid was used without purification 9 g (82%).
63% Product distribution / selectivity; Utilizing the procedure of Thurkauf et al. (J. Med. Chem. 1995, 38, 2251) <strong>[67515-59-7]4-fluoro-3-trifluoromethyl-benzonitrile</strong> (1.89 g, 10 mmol) was converted into 1.30 g (63%) of the title compound as brown oil.
  • 5
  • [ 67515-59-7 ]
  • C27H28F3N5O2 [ No CAS ]
  • 6
  • [ 67515-59-7 ]
  • 1-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)benzyl)-3-(3-aminoisoquinolin-5-yl)urea [ No CAS ]
  • 7
  • [ 67515-59-7 ]
  • C24H26F3N5O3 [ No CAS ]
  • 8
  • [ 67515-59-7 ]
  • N-[4-azepan-1-yl-3-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea [ No CAS ]
  • 10
  • [ 67515-59-7 ]
  • 1-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)benzyl)-3-(1H-indazol-4-yl)urea [ No CAS ]
  • 11
  • [ 67515-59-7 ]
  • [ 735330-63-9 ]
  • 12
  • [ 67515-59-7 ]
  • C24H25F3N4O [ No CAS ]
  • 13
  • [ 67515-59-7 ]
  • [ 635702-33-9 ]
YieldReaction ConditionsOperation in experiment
A solution of 550 mg (2.2 mmol) of [3-TRIFLUOROMETHYL-4- (2- (S)-] methylpropyloxy) benzonitrile (from Step A) in 5 mL of [ETOH] was treated with 1.5 mL of 5.0 N [NAOH] and was heated to [80 C] for 3 h. The reaction was then concentrated, treated with 2 N [HCL,] extracted with 30mL of EtOAc, dried over [MGS04] and concentrated which afforded 600 mg of the title compound [: TH] NMR (500 Mhz) [5] 0.99 (t, J=7.3, 3H), 1.43 (d, J=5.9, 3H), 1.73- 1.83 (m, 2H), 4.54 (septet, 1H), 7.02 (d, J=8.9, 1H), 8.21 (d, J=8.9, 1H), 8.32 (s, [1H).]
  • 14
  • [ 4221-99-2 ]
  • [ 67515-59-7 ]
  • [ 635702-32-8 ]
YieldReaction ConditionsOperation in experiment
CARBOXYLIC ACID 8; 3-Trifluoromethyl-4- (2- (S)-butoxy) benzoic acid; Step A:; 3-Trifluoromethyl-4- (2- (S)-butoxy) benzonitrile; A solution of 1.1 g (5.9 mmol) of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> and 485 mg (6.5 mmol) of (S)- (+)-2-butanol in 10 mL of THF at-10C was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred cold for 2 h, then quenched with 10 mL of H20. The quenched solution was extracted with 30 mL of Et20, dried over MgS04 and concentrated. Chromatography on a Biotage 40M cartridge using 4: 1 v/v hexanes/Ethyl acetate as the eluant afforded 550 mg of the title compound : 1H NMR (500 MHz) 8 0.99 (t, J= 7.6, 3H), 1.35 (d, J= 6.2, 3H), 1.58-1. 83 (m, 2H), 4.51 (septet, 1H), 7.04 (d, J= 8.7, 1H), 7.75 (d, J= 8.7, 1H), 7.85 (s, 1H).
With sodium hydride; In tetrahydrofuran; at -10℃; for 2h; A solution of 1.1 g (5.9 mmol) of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> and 485 mg (6.5 mmol) of (S)-(+)-2-butanol in 10 mL of THF at -lOoC was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred at cold for 2 h, then quenched with 10 mL of H2O. The quenched solution was extracted with 30 mL of Et2theta, dried over MgS O4 and concentrated. Chromatography on a Biotage 4OM cartridge using 4:1 v/v Ixexanes/Ethyl acetate as the eluant afforded 550 mg of the title compound: lH NMR delta 0.99 (t, J = 7.6, 3H), 1.35 (d, J = 6.2, 3H), 1.58 - 1.83 (m, 2H), 4.51 (septet, IH), 7.04 (d, J = 8.7, IH), 7.75 (d, J = 8.7, IH), 7.85 (s, IH).
With sodium hydride; In tetrahydrofuran; at -10℃; for 2h; A solution of 1.1 g (5.9 mmol) [OF 4-FLUORO-3-TRIFLUOROMETHYLBENZONITRILE] and 485 mg (6.5 mmol) of [(S)- (+)-2-BUTANOL] in 10 [ML] [OF THF AT-10 C] was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred cold for 2 h, then quenched with 10 [ML] of [H2O.] The quenched solution was extracted with 30 mL of [ET20,] dried over [MGS04] and concentrated. Chromatography on a Biotage 40M cartridge using 4: 1 v/v hexanes/EtOAc as the eluant afforded 550 mg of the title compound [: IH] NMR (500 Mhz) 8 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58-1. 83 (m, 2H), 4.51 (septet, 1H), 7.04 (d, J=8.7, 1H), 7.75 (d, J=8.7, 1H), 7.85 (s, 1H).
With sodium hydride; In tetrahydrofuran; at -10℃; for 2h; A solution of 1.1 g (5.9 mmol) of 4-fluoro-3- trifluoromethylbenzonitrile and 485 mg (6.5 mmol) of [(S)- (+)-2-BUTANOL] in 10 mL of THE at-10 C was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred cold for 2 h, then quenched with 10 mL of [H2O.] The quenched solution was extracted with 30 mL [OF ET20,] dried over [MGS04] and concentrated. Chromatography on a Biotage 40M cartridge using 4: 1 v/v hexanes/EtOAc as the eluant afforded 550 mg of the title compound [: 1H] NMR (500 Mhz) [5] 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58-1. 83 (m, 2H), 4.51 (septet, 1H), 7.04 (d, J=8.7, 1H), 7.75 (d, J=8.7, 1H), 7.85 (s, 1H).
With sodium hydride; In tetrahydrofuran; at -10℃; for 2h; A solution of 1.1 g (5.9 mmol) of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> and 485 mg (6.5 mmol) of (S)- (+)-2-BUTANOL in 10 mL of THF AT-10C was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred cold for 2 h, then quenched with 10 mL of H2O. The quenched solution was extracted with 30 mL of Et20, dried over MGS04 and concentrated. Chromatography on a Biotage 40M cartridge using 4: 1 v/v hexanes/Ethyl acetate as the eluant afforded 550 mg of the title compound : 1H NMR (500 MHz) 5 0.99 (t, J= 7.6, 3H), 1.35 (d, J= 6.2, 3H), 1.58-1. 83 (m, 2H), 4. 51 (septet, 1H), 7.04 (d, J= 8.7, 1H), 7.75 (d, J= 8.7, 1H), 7.85 (s, 1H).

  • 15
  • [ 67515-59-7 ]
  • [ 111-42-2 ]
  • [ 1100712-21-7 ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl acetamide; at 50℃; for 168h; A solution of 3-trifluoromethyl 4-fluoro-benzonitrile (9.45 g, 50 mmol) and diethanolamine (15.8 g, 0.15 mol) in N,N-dimethylacetamide (200 ml) was stirred for 7 days at 50C. The solvent was evaporated, the residue partitioned between CH2Cl2 (400 ml) and H2O (400 ml), the organic layer dried (MgSO4) and evaporated to dryness. The residue was chromatographed using CH2Cl2-EtOH as eluent.
  • 16
  • [ 67515-59-7 ]
  • [ 1752-88-1 ]
  • [ 864297-32-5 ]
YieldReaction ConditionsOperation in experiment
43% 1.00 g (5.29 mmol) <strong>[67515-59-7]4-fluoro-3-trifluoromethyl-benzonitrile</strong> are stirred together with 1.35 g (12.0 mmol) potassium-tert.-butoxide in 4 ml DMSO at ambient temperature under an argon atmosphere for 35 min and then 1.00 g (8.16 mmol) pyrazolidin-3-on-hydrochloride in 3 ml DMSO are added. After stirring at ambient temperature for 68 h the reaction mixture is poured into semisat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down completely i. vac. Yield: 0.58 g (43%) C11H8F3N3O (255.20) Mass spectrum: (M+H)+=256 Rf value: 0.15 (silica gel; dichloromethane+0.5% conc. ammonia solution)
  • 17
  • [ 110-85-0 ]
  • [ 67515-59-7 ]
  • [ 773849-16-4 ]
YieldReaction ConditionsOperation in experiment
100% 37.9 g (195 mmol) piperazine hexahydrate are refluxed for 2 hours with 12.4 g (66 mmol) <strong>[67515-59-7]4-fluoro-3-trifluoromethyl-benzonitrile</strong> suspended in 40 ml of ethanol. Then 13.7 ml (261 mmol) 50% sodium hydroxide solution and 13.7 ml of water are added and the mixture is refluxed for a further 3.5 hours and kept at ambient temperature for a further 15 hours. Then 43.5 ml of conc. hydrochloric acid are added and the mixture is cooled to 10 C. for 30 minutes with stirring. The precipitate obtained is suction filtered, washed with a little water and dried at 40 C. in the circulating air dryer for 24 hours. Yield: 20.8 g (quantitative)
  • 18
  • [ 10004-17-8 ]
  • [ 67515-59-7 ]
  • [ 871795-91-4 ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.5h; Example 1: 4-f2-cvano-2-(4-trif)uoromethoxvbenzoyiamino)-1 -propoxy]-3- trifluoromethylbenzamide a) In 30 ml of tetrahydrofuran 1.13 g of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> and 1.87 g of (2-methyl-2-hydoxymethyl-[1,3]dioxolan are diluted and cooled to 0C. Then a cold solution of 0.73 g potassium t-butoxide in tetrahydrofuran is added dropwise. After stirring for 30 min at 0C the reaction mixture is diluted with 50 ml of ethyl acetate and washed twice with a saturated solution of ammonium chloride, water and brine. The organic phase is finally dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is then stirred with hexane, filtered and dried to yield amorphous crystals of 4-(2-methyl-[1,3]dioxolan-2- ylmethoxy] )-3-trifluoromethylbenzonitrile.
  • 19
  • [ 67515-59-7 ]
  • [ 4344-87-0 ]
  • 3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
42.4% With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 6h; Potassium carbonate (2.8 g, 20.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (1.47 g, 15.0 mmol) and <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> (2.8 g, 15.0 mmol) in DMF (30 ml), and the mixture was stirred under heating at 80C for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (70 ml) and extracted with ethyl acetate (30 ml x 3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane = 1/5), to give a yellowish solid of 3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole (1.7 g, yield: 42.4 %). mp: 123-125C; 1H-NMR(CDCl3, TMS, ppm): delta 2.28(d, J=0.5Hz, 3H), 5.75(d, J=0.5Hz, 1H), 7.30(d, J=8.8Hz, 1H), 7.75(dd, J=2.0 and 8.8Hz, 1H), 7.96(d, J=2.0Hz, 1H), 9.60-11.60(br s, 1H).
  • 20
  • [ 3752-24-7 ]
  • [ 67515-59-7 ]
  • [ 720000-06-6 ]
  • 21
  • [ 67515-59-7 ]
  • [ 20277-69-4 ]
  • [ 904311-38-2 ]
YieldReaction ConditionsOperation in experiment
100% In dimethyl sulfoxide; at 80℃; for 22h; <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (400 mg, 2.12 mmol) was suspended together with sodium methanesulfinate (216 mg, 2.12 mmol) in DMSO (2 ml) and stirred at 800C for 22 hours. The reaction was then cooled, diluted with 25 ml H2O and filtered. Filtered solids were evaporated from toluene to give 536 mg of the title substance (quant).1H NMR (CDCl3) delta 8.49 (d, IH), 8.20 (s, IH), 8.10 (d, IH), 3.24 (s, 3H).
100% In dimethyl sulfoxide; at 80℃; for 22h; 4-(Methylsulfonyl)-3-(trifluoromethyl)benzonitrile <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (400 mg, 2.12 mmol) was suspended together with sodium methanesulfinate (216 mg, 2.12 mmol) in DMSO (2 ml) and stirred at 80 C. for 22 hours. The reaction was then cooled, diluted with 25 ml H2O and filtered. Filtered solids were evaporated from toluene to give 536 mg of the title substance (quant). 1H NMR (CDCl3) delta 8.49 (d, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 3.24 (s, 3H).
90% In N,N-dimethyl-formamide; at 100℃; for 2h; A mixture of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> (75 mg, 0.40 mmol), sodium sulfinate (44.5 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL) was heated at 100 C. for 2 h. The reaction mixture was cooled to room temperature, quenched with water. The resulting white solid was collected via filtration, washed with cold water, dried in a vacuum oven to give 4-methanesulfonyl-3-trifluoromethyl-benzonitrile (90 mg, 90% yield). This benzonitrile was hydrogenated in 2N NH3 in methanol with 35 mg of Raney Ni under a hydrogen balloon for 2 h. The reaction mixture was filtered through a celite plug, washed with methanol, evaporated in vacuo to give the titled compound.
  • 22
  • [ 905724-78-9 ]
  • [ 67515-59-7 ]
  • C21H15F3N2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl acetamide; at 90℃; for 0.5h; INTERMEDIATE 2 (132 mg, 0.5 mmol) was combined with 2-trifluoromethyl-4-fluorobenzonitrile (103 mg, 0.5 mmol) and Cs2CO3 (1.0 g, 3 mmol) in 5 mL of N,N-dimethylacetamide. The reaction mixture was stirred at 90 0C for 30 min, then was dumped into water and acidified with 2N aq. HCl to pH <2. The resulting solid precipitate was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexane gradient) gave the product. LC-MS calc. for C21H15F3N2O3S: 432; Found: 433 (M+H).
  • 23
  • [ 905724-75-6 ]
  • [ 67515-59-7 ]
  • C20H13F3N2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl acetamide; at 90℃; for 0.5h; INTERMEDIATE 1 (755 mg, 0.3 mmol) was combined with 2-trifluoromethyl-4-fluorobenzonitrile (72 mg, 0.3 mmol) and Cs2CO3 (1.0 g, 3 mmol) in 5 mL of N,N-dimethylacetamide. The reaction mixture was stirred at 90 0C for 30 min, then was dumped into water and acidified with 2N aq. HCl to pH <2. The resulting solid precipitate was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexane gradient) gave the product. LC-MS calc. for C20H13F3N2O3S: 418; Found: 419 (M+H).
  • 24
  • [ 67515-59-7 ]
  • [ 538-09-0 ]
  • 4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-trifluoromethylbenzo-nitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% With pyridine; at 110℃; for 20h; Example 25 4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-trifluoromethylbenzo-nitrile (196MBT10-B) Nortropine (269 mg, 2.12 mmol) and <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)benzonitrile</strong> (100 mg, 0.529 mmol) were dissolved in pyridine (2 mL). The mixture was heated to 110 C. in a sealed flask for 20 hours and then concentrated. The residue was dissolved in 2 M HCl (20 mL) and extracted with dichloromethane (2×20 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated, and the resulting oil was purified by preparative TLC (eluting with dichloromethane) to afford 55 mg (35%) of the title compound as a colorless solid. LCMS m/z 297 [M+H]+. 1H-NMR (CDCl3) delta 7.80-6.85 (m, 3H), 4.15-4.00 (m, 3H), 2.33-2.10 (m, 4H), 2.00-1.84 (m, 2H), 1.82-1.70 (m, 2H), 1.39 (s, 1H).
  • 25
  • [ 507237-50-5 ]
  • [ 67515-59-7 ]
  • [ 507239-93-2 ]
YieldReaction ConditionsOperation in experiment
Example 45 4-(2-Methyl-4-pyrrolidin-1-yl-quinolin-7-ylmethoxy)-3-trifluoromethyl-benzonitrile The title compound was produced in accordance with the general method of example 6 from (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanol (example 2) and <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong>. Light yellow solid, ISP-MS: m/e=412.4 ([M+H]+).
  • 26
  • [ 507237-46-9 ]
  • [ 67515-59-7 ]
  • [ 507241-08-9 ]
YieldReaction ConditionsOperation in experiment
a 4-(4-Chloro-2-methyl-quinolin-7-ylmethoxy)-3-trifluoromethyl-benzonitrile The title compound was produced in accordance with the general method of example 54a from (4-chloro-2-methyl-quinolin-7-yl)-methanol (example 2c) and <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong>. Off-white solid, ISP-MS: m/e=377.3 ([M+H]+).
  • 27
  • [ 507240-56-4 ]
  • [ 67515-59-7 ]
  • [ 507241-28-3 ]
YieldReaction ConditionsOperation in experiment
Example 71 4-(2,6-Dimethyl-4-pyrrolidin-1-yl-quinolin-7-ylmethoxy)-3-trifluoromethyl-benzonitrile The title compound was produced in accordance with the general method of example 6 from (2,6-dimethyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanol (example 59c) and <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong>. Light yellow solid, ISP-MS: m/e=426.4 ([M+H]+).
  • 28
  • [ 67515-59-7 ]
  • (2-trifluoromethyl-4-cyano-phenyl)-hydrazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With hydrazine hydrate; a. (2-trifluoromethyl-4-cyano-phenyl)-hydrazine Prepared analogously to Example 5a from <strong>[67515-59-7]4-fluoro-3-trifluoromethyl-benzonitrile</strong> and hydrazine hydrate. Yield: 89% of theory, Rf value: 0.56 (silica gel; petroleum ether/ethyl acetate=4:1)
  • 29
  • [ 67515-59-7 ]
  • 4-hydrazino-3-trifluoromethyl-benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With hydrazine hydrate; a. 4-hydrazino-3-trifluoromethyl-benzoic acid Prepared analogously to Example 5.a. from <strong>[67515-59-7]4-fluoro-3-trifluoromethyl-benzonitrile</strong> and hydrazine hydrate. Yield: 79% of theory, Rf value: 0.21 (silica gel; cyclohexane/ethyl acetate=2:1+1% glacial acetic acid)
  • 30
  • 3-dimethoxymethyl-1,4,5,6-tetrahydro-cyclopentapyrazole [ No CAS ]
  • [ 67515-59-7 ]
  • 3-dimethoxymethyl-1-(2-trifluoromethyl-4-cyano-phenyl)-1,4,5,6-tetrahydro-cyclopentapyrazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
In N-methyl-acetamide; b. 3-Dimethoxymethyl-1-(2-trifluoromethyl-4-cyano-phenyl)-1,4,5,6-tetrahydro-cyclopentapyrazole 0.7 g (17.5 mmol) of sodium hydride are added at 0 C. to a solution of 3.2 g (17 mmol) of <strong>[67515-59-7]4-fluoro-3-trifluoromethyl-benzonitrile</strong> and 3.1 g (17 mmol) of 3-dimethoxymethyl-1,4,5,6-tetrahydro-cyclopentapyrazole in 20 ml of dimethylformamide. After 3 hours at ambient temperature the reaction solution is poured onto ice water and extracted with ethyl acetate. The organic phase is washed with water and with saturated saline solution, dried and evaporated down. The crude product is recrystallized from diisopropylether/petroleum ether. Yield: 3.2 g (54% of theory) Rf value: 0.33 (silica gel; petroleum ether/ethyl acetate=7:3+1% conc. ammonia)
  • 31
  • [ 3752-24-7 ]
  • [ 67515-59-7 ]
  • 4-(4,5,6,7-tetrahydro-benzimidazol-1-yl)-3-methyl-benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% a. 4-(4,5,6,7-tetrahydro-benzimidazol-1-yl)-3-methyl-benzonitrile Prepared analogously to Example 4.a. from 3-trifluoromethyl-4-fluoro-benzonitrile and 4,5,6,7-tetrahydro-benzimidazole. Yield: 88% of theory, Rf value: 0.36 (silica gel; ethyl acetate)
  • 32
  • [ 67515-59-7 ]
  • [ 108-46-3 ]
  • [ 163301-17-5 ]
YieldReaction ConditionsOperation in experiment
18-crown-6 ether; In acetonitrile; (a) 40% Potassium fluoride-alumina (3 g) and 0.4 g of 18-crown-6-ether were added to 50 ml of acetonitrile solution containing 1.55 g of resorcinol and 5.34 g of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong>. After heating the reaction mixture overnight under reflux, insoluble materials were separated by filtration, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was recrystallized from hexane-ethyl acetate to obtain 2.40 g of 1,3-bis(4-cyano-2-trifluoromethylphenoxy)benzene. Mass spectrometry data (m/z): 449 ([M+H]+)
  • 33
  • [ 106-52-5 ]
  • [ 67515-59-7 ]
  • [ 859213-08-4 ]
YieldReaction ConditionsOperation in experiment
54% With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1.16667h; 14) l-[4-[(l-Methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)phenyl]ethanamineA.4-[(l -Methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)benzonitrile A mixture of 4-hydroxy-iV-methylpiperidine (133 mg, 1.15 mmol) and potassium tert-bu- toxide (150 mg, 1.27 mmol) in tetrahydrofuran (2.5 mL) was stirred under nitrogen for 10 min. <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (218 mg, 1.15 mmol) was added, and the 5 reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo, and the residue was partitioned between a 1 M NaOH solution and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3/MeOH/conc. NH3, 95:5:0.5) affording 0.18 g (54% yield) of the pure product as a colourless solid. MS (APCI) m/z 285 [M+H]. 1H NMR o (400 MHz, DMSO-D6) delta ppm 1.67-1.74 (m, 2 H), 1.89-1.95 (m, 2 H), 2.16 (s, 3 H), 2.26- 2.31 (m, 2 H), 2.44-2.48 (m, 2 H), 4.78-4.82 (m, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 8.08 (dd, J = 8.8, 2.0 Hz, 1 H), 8.14 (d, J = 2.0 Hz, 1 H).
Step 1 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethylbenzonitrile 6.68 g of potassium t-butoxide was suspended in 40 ml of anhydrous tetrahydrofuran and a solution of 6.85 g of 1-methyl-4-hydroxypiperidine in 20 ml of anhydrous tetrahydrofuran was added dropwise over 35 minutes while stirring under ice-water cooling and further the mixture was stirred for 30 minutes. On the other hand, 7.50 g of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> was dissolved in 40 ml of anhydrous tetrahydrofuran, the mixture was stirred under cooling in a dry ice/acetone bath, and the solution prepared earlier was added dropwise at the internal temperature of -70C. After adding dropwise, the reaction solution was stirred overnight while naturally heating up to room temperature. The reaction solution was ice-cooled, an aqueous saturated ammonium chloride solution and water were added thereto, and then the solvent was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate twice. The extracts were washed in turn with water and saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.31 g of the objective compound as colorless crystals. Melting point: 66-69C
  • 34
  • [ 110-91-8 ]
  • [ 67515-59-7 ]
  • [ 677704-57-3 ]
YieldReaction ConditionsOperation in experiment
95% at 60℃; for 8h; A mixture of 4-fluoro-3-trifluoro-methylbenzonitrile (Fluorochem 2223; 10 g; 52.8 mmol; 1 eq.) and morpholine (Fluka 69880; 9.25 ml 105.7 mmol; 2 eq.) was stirred at 600C for 8 hours. The mixture was cooled and diluted with water. The precipitate was filtered and dried to afford the title compound (12.9 g, 95%) as a white solid. HPLC (Method B) : Rt 3.61 min (purity 99.1 %). LC/MS : 257.1 (M+H)+. 1H NMR (CDCI3, 400MHz) delta 7.92 (1 H, s), 7.78-7.81 (1 H, d), 7.32-7.35 (1 H, d), 3.84-3.87 (4H, m), 3.04-3.06 (4H, m).
95% at 60℃; for 8h; A mixture of 4-fluoro-3-trifluro-methylbenzonitrile (Fluorochem2223, 10 g, 52.8 mmol) and morpholine (9.25ml_, 105.7 mmol) was heated at 6O C under N2 for 8 hours. The mixture was cooled and diluted with water (100 ml_). The precipitate was filtered affording the title compound as a white solid (12.9 g, 95%). 1H NMR (CDCI3, 400 MHz) delta 7.92 (s, 1 H), 7.78- 7.81 (d, 1 H), 7.32-7.35 (d, 1 H), 3.84-3.87 (m, 4H), 3.04-3.06 (m, 4H). LC/MS (Method A): 257.1 (M+H)+. HPLC (Method B) Rt 3.61 min (Purity: 99.1%).
85% In dimethyl sulfoxide; at 90℃; for 18h; Preparation No.11: 4-morpholino-3-(trifluoromethyl)benzonitrile; To a solution of <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)benzonitrile</strong> (15 g, 79 mmol) in dimethylsulfoxide (160 mL) was added morpholine (13.8 mL, 159 mmol) and potassium carbonate (16.4 g, 119 mmol). The mixture was heated at about 900C for 18 hours. The mixture was cooled to ambient temperature and the solid was removed by filtration. The fitrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed with water (1.0 L) and brine (1.0 L) and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to give 4-morpholino-3-(trifluoromethyl)benzonitrile (17.25 g, 85 %). 1H NMR (DMSO-lambda6, 400MHz) delta 8.18 (d, J = 2.05 Hz, IH), 8.09 (dd, J = 8.51, 2.06 Hz, IH), 7.60 (d, J = 8.52 Hz, IH), 3.69-3.75 (m, 4H), 2.97-3.04 (m, 4H).
85% With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 18h; Preparation No.16: 4-morpholino-3-(trifluoromethyl)benzonitrile; To a solution of <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)benzonitrile</strong> (15 g, 79 mmol) in dimethylsulfoxide (160 mL) was added morpholine (13.8 mL, 159 mmol) and potassium carbonate (16.4 g, 1 19 mmol). The mixture was heated at about 90 C for about 18 h. The mixture was cooled to ambient temperature and the solid was removed by filtration. The filtrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed with water (1.0 L) and brine (1.0 L) and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to give 4-morpholino-3-(trifluoromethyl)benzonitrile (17.25 g, 85 %). .H NMR (DMSO-J6, 400MHz) delta ppm 8.18 (d, J = 2.05 Hz, 1H), 8.09 (dd, J = 8.51 , 2.06 Hz, 1H), 7.60 (d, J = 8.52 Hz, 1H), 3.69-3.75 (m, 4H), 2.97-3.04 (m, 4H).
80% With potassium carbonate; In dimethyl sulfoxide; at 90℃; K2CO3 (2.0 eq.) and 2.0 equiv. of the corresponding nucleophile (Nu in scheme 16) were added to a solution of <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)benzonitrile</strong> (1.0 eq.) in DMSO. The mixture was heated at 90 0C overnight. The mixture was cooled to r.t. and the solids were removed by filtration. Water was added to the filtrate and the product was precipitated, collected by filtration, washed with water and dried under vacuum.The following substances were synthesized following general procedure D for the nucleophilic aromatic substitution of <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)-benzonitrile</strong>. The solvent system used for the purification, the yield and analytical data is given for each compound. Yield: 80%1H NMR (CDCl3) delta 7.92 (d, IH), 7.79 (m, IH), 7.33 (d, IH), 3.86 (m, 4H), 3.95 (m, 4H)
80% With potassium carbonate; In dimethyl sulfoxide; at 90℃; General Procedure D for the Nucleophilic Aromatic Substitution of <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)-benzonitrile</strong> (see Scheme 16 Above).K2CO3 (2.0 eq.) and 2.0 equiv. of the corresponding nucleophile (Nu in scheme 16) were added to a solution of <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)benzonitrile</strong> (1.0 eq.) in DMSO. The mixture was heated at 90 C. overnight. The mixture was cooled to r.t. and the solids were removed by filtration. Water was added to the filtrate and the product was precipitated, collected by filtration, washed with water and dried under vacuum.The following substances were synthesized following general procedure D for the nucleophilic aromatic substitution of <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)-benzonitrile</strong>. The solvent system used for the purification, the yield and analytical data is given for each compound.4-Morpholino-3-(trifluoromethyl)benzonitrileYield: 80% 1H NMR (CDCl3) delta 7.92 (d, 1H), 7.79 (m, 1H), 7.33 (d, 1H), 3.86 (m, 4H), 3.95 (m, 4H)
In ISOPROPYLAMIDE; at 145℃; for 19h; <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (2.0g, 10.58mmol) was dissolved in dimethyl acetamide (35mL), morpholine (2.88mL, 31.73mmol) was added thereto, and the mixture was subjected to a reaction at 145C for 19 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50mL), and the organic layer was washed with an aqueous sodium hydrogen carbonate solution (50mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was crystallized with ethyl acetate (lOmL) and n-hexane (80mL) to obtain the title compound as a brown solid (2.1g).1H NMR (DMSO-d6) delta 8.17 (s, 1H), 8.08 (d, 1H), 7.58 (d, 1H), 3.71 (m, 4H), 2.99 (m, 4H).
2.1 g In N,N-dimethyl acetamide; at 145℃; for 19h; <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (2.0 g, 10.58 mmol) was dissolved in dimethyl acetamide (35 mL), morpholine (2.88 mL, 31.73 mmol) was added thereto, and the mixture was subjected to a reaction at 145 C. for 19 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and the organic layer was washed with an aqueous sodium hydrogen carbonate solution (50 mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was crystallized with ethyl acetate (10 mL) and n-hexane (80 mL) to obtain the title compound as a brown solid (2.1 g). 1H NMR (DMSO-d6) delta 8.17 (s, 1H), 8.08 (d, 1H), 7.58 (d, 1H), 3.71 (m, 4H), 2.99 (m, 4H).

  • 35
  • [ 1046820-87-4 ]
  • [ 67515-59-7 ]
  • [ 1046820-85-2 ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 19h; To a mixture of the compound of Preparation 9 (150 mg, 0.5 mmol) and <strong>[67515-59-7]4-fluoro-3-(trifluoromethyl)benzonitrile</strong> (86 mg, 0.5 mmol), under nitrogen, was added tetrahydrofuran (2 ml). The mixture was cooled to 0 C., before the dropwise addition of potassium tert-butoxide (1M in tetrahydrofuran, 0.8 ml, 0.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 19 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution (×2), water and brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in methanol (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×50 mm LUNA C18(2) 10 mum column, 120 ml/min) using an acetonitrile:water gradient [55:45 (for 15 min) to 98:2 (for 3 min) to 55:45 (for 1 min)]. The appropriate fractions were concentrated in vacuo to give the compound of Example 3a (73 mg) as a racemic mixture.Experimental MH+ 499.9; expected 500.11H-NMR (d6-Acetone): 1.98-2.00 (3H), 4.78-4.80 (1H), 4.84-4.86 (1H), 7.58-7.60 (1H), 8.00-8.03 (2H), 8.08-8.12 (4H)in vitro H.c. (L3) MED=1 mug/ml
 

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