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Chemical Structure| 6226-25-1 Chemical Structure| 6226-25-1

Structure of 2,2,2-Trifluoroethyl triflate
CAS No.: 6226-25-1

Chemical Structure| 6226-25-1

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Product Details of [ 6226-25-1 ]

CAS No. :6226-25-1
Formula : C3H2F6O3S
M.W : 232.10
SMILES Code : C(O[S](C(F)(F)F)(=O)=O)C(F)(F)F
MDL No. :MFCD00671579
InChI Key :RTMMSCJWQYWMNK-UHFFFAOYSA-N
Pubchem ID :80366

Safety of [ 6226-25-1 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301-H314-H330
Precautionary Statements:P260-P280-P284-P301+P310-P305+P351+P338-P310
Class:8(6.1)
UN#:2922
Packing Group:

Computational Chemistry of [ 6226-25-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 4
Num. H-bond acceptors 9.0
Num. H-bond donors 0.0
Molar Refractivity 26.97
TPSA ?

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

51.75 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.46
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

1.97
Log Po/w (WLOGP)?

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

5.02
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.

1.1
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

1.9
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.29

Water Solubility

Log S (ESOL):?

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

-2.26
Solubility 1.29 mg/ml ; 0.00554 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.

-2.68
Solubility 0.482 mg/ml ; 0.00208 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

-1.73
Solubility 4.31 mg/ml ; 0.0186 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.

-6.32 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

2.0 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)

2.57

Application In Synthesis of [ 6226-25-1 ]

* 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 [ 6226-25-1 ]

[ 6226-25-1 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 6226-25-1 ]
  • [ 13599-12-7 ]
  • [ 939377-23-8 ]
YieldReaction ConditionsOperation in experiment
52% Preparation of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid To a mixture of <strong>[13599-12-7]5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester</strong> (500 mg, 2.31 mmol) in N,N-dimethylformamide (30 mL) at 0° C. was added sodium hydride (60percent in mineral oil, 110 mg, 2.75 mmol). The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 40 minutes. After the reaction mixture was re-cooled to 0° C., 2,2,2-trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (500 mg, 2.39 mmol) was added dropwise. The mixture was warmed up to room temperature and stirred overnight. The reaction was quenched carefully with ice water and neutralized with 1N aqueous hydrochloric acid. The mixture was extracted with methylene chloride and the organic layer was dried over sodium sulfate. Filtration and concentration gave a crude which was purified by silica gel chromatography (Isco 120 g column, 11percent ethyl acetate/hexanes) to give 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (360 mg, 52percent) as a white solid. The NMR spectrum obtained on the sample is compatible with its structure. A mixture of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (360 mg, 1.21 mmol) and 1N aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH~2 with 1N aqueous hydrochloric acid and concentrated to give 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid as an off-white solid, which was directly used in the next step reaction without further purification. LCMS calcd for C12H9F3N2O (m/e) 270, obsd 271 (M+H).
  • 2
  • [ 269410-08-4 ]
  • [ 6226-25-1 ]
  • [ 1049730-42-8 ]
YieldReaction ConditionsOperation in experiment
78% With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 100℃; for 2h; To a stirred solution of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 Hpyrazole (100 mg, 0.5 15 mmol) in DMF (1 ml) were added Cs2CO3 (252 mg, 0.773mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.144 ml, 1.031 mmol) at rt. After stirring at 100 C for 2 h, the reaction mixture was evaporated to dryness, partitioned between EtOAc and water, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 4-(4,4,5,5-tetramethyl-i,3,2- dioxaborolan-2-yl)- 1 -(2,2,2-trifluoroethyl)- 1 H-pyrazole (0.111 g, 78% yield). MS(ESI)m/z: 277.4 (M+H).
76% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.833333h; To a solution of 4-(4, 4,5,5, -tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 H-pyrazole (250 mg, 1.29 mmol) in N,N-dimethylformamide (4 mL) were added cesium carbonate (630 mg, 1.93 mmol) and 2,2,2-trifluoroethyl trifluoro methanesulfonate (0.37 mL, 2.58 mmol). The mixture was stirred at 100C for 50 minutes. The mixture was then poured in water (15 mL) and extracted with ethyl acetate (2x10 mL). The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (10 mL), brine (10 mL), dried over sodium sulfate and concentrated in vacuo to provide 4-(4, 4,5,5,- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -(2,2,2-trifluoroethyl)-1 H-pyrazole (22a) (271 mg, 0.98 mmol, 76%) which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 1.32 (s, 12H), 4.71 (q, J = 8.4 Hz, 2H), 7.80 (s, 1 H), 7.84 (s, 1 H).
64% With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h; 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.66 g, 2.86 mmol, 0.4 mL) was added to a mixture of 4-(4,4,5,5-tetramethyl-i ,3,2-dioxaborolan-2-yl)-i H-pyrazole (0.46 g, 2.37 mmol) and cesium carbonate (1.60 g, 4.92 mmol) in dry N,N-dimethylformamide (10.0 mL) at 0C. After stirring for 30 mm the reaction mixture was allowed to warm to room temperature. After stirring for 3 h the reaction mixture was poured out into water (200 mL) and the mixture was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (3x100 mL) and brine and were dried with sodium sulfate. Solvents were removed in vacuo to afford 0.42 g (1.51 mmol; 64% of theory) of the title compound.GO-MS (Method L9): R1 = 3.36 mm; m/z = 276 M
62% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 15h; To a stirred solution of 4-(4,4,5,5-tetramethyl- I ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 10.3 mmcl) in DMF (20 ml) was added potassium carbonate (4.27 g, 30.9 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.2 ml, 15 mmcl). The mixture was stirred at 80C for14 h. Further 2,2,2-trifluoroethyl trifluoromethanesulfonate (420 p1, 2.9 mmcl) was added and the mixture was stirred at 80C for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagelchromatography gave 1.76 g (62 % yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6) oe [ppm]: 1.066 (1.33), 1.256 (16.00), 5.144 (0.85), 5.167 (0.81),7.701 (1.31), 8.055 (1.26).
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.5h;Inert atmosphere; Intermediate 14: 4-(4,4,5,5-Tetramethyl-1 , 3,2-dioxaborolan-2-yl)-1 -(2,2,2- trif luoroethyl)-1 H-pyrazole; 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.7g, 124mmol) (Apollo Scientific) was added to a mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (20g, 103mmol) (Aldrich) and cesium carbonate (67.2g, 206mmol) in N,N- Dimethylformamide (DMF) (150ml) at 0C under nitrogen . The mixture was stirred for 30 min at 0C then allowed to warm to room temperature and stirred for a further 2h. The mixture was quenched with water (200ml) and extracted with EtOAc (200ml). The organic layer was washed with water (200ml), dried and evaporated to give a brown oil. This was dissolved in DCM (30ml), the fine precipitate was filtered off and the filtrate loaded onto a 330g silica column, then eluted with 0-50% EtOAc/cyclohexane. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (14.7g)1 H NMR (CDCI3) 7.86ppm (1 H, s, CH); 7.82ppm (1 H, s, CH); 4.73ppm ( 2H, q, CH2); 1.34ppm (12H, s, 4xCH3).
14.7 g With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; Intermediate 14: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.7 g, 124 mmol) (Apollo Scientific) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20 g, 103 mmol) (Aldrich) and cesium carbonate (67.2 g, 206 mmol) in N,N-Dimethylformamide (DMF) (150 ml) at 0 C. under nitrogen. The mixture was stirred for 30 min at 0 C. then allowed to warm to room temperature and stirred for a further 2 h. The mixture was quenched with water (200 ml) and extracted with EtOAc (200 ml). The organic layer was washed with water (200 ml), dried and evaporated to give a brown oil. This was dissolved in DCM (30 ml), the fine precipitate was filtered off and the filtrate loaded onto a 330 g silica column, then eluted with 0-50% EtOAc/cyclohexane. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (14.7 g) 1H NMR (CDCl3) 7.86 ppm (1H, s, CH); 7.82 ppm (1H, s, CH); 4.73 ppm (2H, q, CH2); 1.34 ppm (12H, s, 4*CH3).
The following Preparations were prepared according to Method H (Preparation 122) using 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole and the appropriate alkyl electrophile.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; . Sodium hydride (61.8 mg, 1.55 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (150 mg, 0.77 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (269 mg, 1.16 mmol) in DMF (5 ml) at 0C and the mixture was stirred at 20C for 12 h. The mixture was quenched with aqueous saturated ammonium chloride (6 mL) and extracted with ethyl acetate (3 x 8 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)- lH-pyrazole. MS (ESI) calc'd for (C11H17BF3N2O2) [M+H]+, 277 ; found, 277
With caesium carbonate; In 1,4-dioxane; at 20℃; for 3.5h; [00771] Compound 50 was prepared in 2 steps according to the following procedures: 4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1H-pyrazole (2.6 mmol, 1.0 equiv) and cesium carbonate (2.0 equiv) were suspended in dioxane (10 mL). Trifluoroethyltriflate (1.24 equiv) was added and the reaction was stirred at room temperature for 3 .5h after which the mixture partionned between water and brine and extracted with ethyl acetate. The combined organics were concentrated onto silica gel (4g) and purified using flash silica gel chromatography (Silicycle Si-40g, gradient 10-100% ethyl acetate/hexanes) to provide pinacol ester 49.
Step 1: 4-(4,4, 5,5-Tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 -(2 ,2,2-trifl uoroethyl)- 1 H-pyrazole Cesium carbonate (3.36 g, 10.31 mmol) was added to a stirred solution of 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol) in dry DMF (12 ml).After stirring at RT for 10 mm 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.11 ml, 7.73 mmol) was added. The reaction was stirred for 2 days at RT then the solvent was removed and the residue was partitioned between diethyl ether and water. The organic extract was separated, dried over MgSO4 and the solvent removed to give an oil;LCMS: Rt 1.00 mins; MS MS mlz 277.4 [M+H]+; Method 2minLCvOO3
With caesium carbonate; In acetonitrile; at 60℃; for 2h; Intermediate D1 4-(4,4,5,5-Tetramethyl-1,3,2-dioxoborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-pyrazoleA stirred mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.56 g, 2.89 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.633 ml, 4.39 mmol) and cesium carbonate (2.81 g, 8.62 mmol) in acetonitrile (20 ml) was heated at 60C. After 2h the solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic extract was dried over MgS04 and the solvent was removed under reduced pressure to afford the title compound as a gum;LCMS: Rt 1.00 mins; MS m/z 277.4 [M+H]+; Method 2minl_C_v0031H NMR (400MHz, CDCI3) delta 7.88 (1 H, s), 7.82 (1 H, s), 4.73 (2H, q), 1.35 (12H, s).
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; Intermediate 255A: 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l -(2,2,2- trifluoroethyl)- lH-pyrazole To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (400 mg, 2.06 mmol) in DMF (2 mL) was added CS2CO3 (1.0 g mg, 3.1 mmol) and 2,2,2-trifluoroethyl triflate (0.58 mL, 4.1 mmol). The mixture was heated at 100 C for 2 hours. After cooling, the mixture was concentrated to dryness then partitioned between EtOAc and water. The layers were separated and the organic layer was dried over Na2S04, filtered, and concentrated to afford the crude product which was used directly in the next step. NMR (400 MHz, CHLOROFORM-^ delta 7.85 (s, 1 H) 7.80 (s; 1 H) 4.64-4.76 (m, 2 H), 1.32 (s, 12 H).

  • 3
  • [ 1052114-81-4 ]
  • [ 6226-25-1 ]
  • [ 1449300-95-1 ]
YieldReaction ConditionsOperation in experiment
123 mg With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; 2,2,2-Trifluoroethyl trifluoromethanesulfonate (371 mul) was added to a suspension of <strong>[1052114-81-4]5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid</strong> (100 mg) and cesium carbonate (838 mg) in DMF (2 ml) at room temperature. The reaction mixture was stirred at room temperature for three hours and diluted by adding ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by PLC [ethyl acetate:hexane=2:1 (v/v)] to give 123 mg of the title compound as a solid. 1H-NMR (CDCl3) delta: 4.37-4.46 (2H, m), 4.65-4.71 (2H, m), 7.05-7.12 (2H, m), 7.34-7.39 (1H, m), 7.49-7.56 (2H, m), 8.16 (1H, d, J=2.4 Hz). MS (ESI) m/z: 398 (M+H)+.
  • 4
  • [ 6226-25-1 ]
  • [ 78208-72-7 ]
  • [ 1620412-28-3 ]
  • [ 1620412-29-4 ]
YieldReaction ConditionsOperation in experiment
54%; 20% NaH (1.23 g, 31.15 mmol) was dissolved in DMF (200 mL) under 2 atmosphere at 0 °C. To this solution was added <strong>[78208-72-7]ethyl 5-isopropylpyrazole-3-carboxylate</strong> (5.16 g, 28.33 mmol) in DMF (50 mL) over 10 min at 0 °C. After the addition, the r.m. was stirred for 10 min at 0 °C and then at r.t. for 40 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (4.5 mL, 31.15 mmol) was subsequently added and the mixture was stirred at r.t. for 3 h. After this time the rm was quenched by addition of EtOH at 0 °C. Water was added to the mixture and the water layer was extracted with EtOAc. The organic layer was then washed with brine, dried (MgS04), filtered and concentrated in vacuo. The resulting crude was purified by flash column chromatography (silica; heptanes/EtOAc 100/0 to 60/40) to afford intermediate 42 (4.05 g, 54percent) and regioisomer intermediate 43 (1.52 g, 20percent).
54%; 20% NaH (1.23 g, 31.15 mmol) was dissolved in DMF (200 mL) under N2 atmosphere at 0° C. To this solution was added <strong>[78208-72-7]ethyl 5-isopropylpyrazole-3-carboxylate</strong> (5.16 g, 28.33 mmol) in DMF (50 mL) over 10 min at 0° C. After the addition, the r.m. was stirred for 10 min at 0° C. and then at r.t. for 40 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (4.5 mL, 31.15 mmol) was subsequently added and the mixture was stirred at r.t. for 3 h. After this time the rm was quenched by addition of EtOH at 0° C. Water was added to the mixture and the water layer was extracted with EtOAc. The organic layer was then washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting crude was purified by flash column chromatography (silica; heptanes/EtOAc 100/0 to 60/40) to afford intermediate 42 (4.05 g, 54percent) and regioisomer intermediate 43 (1.52 g, 20percent).
  • 5
  • [ 6226-25-1 ]
  • [ 18650-39-0 ]
  • C9H14F3NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.385 g With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 24h; A solution of (S)-methyl piperidine-2-carboxylate, HC1 (0.5 g, 2.78 mmol),2,2,2-trifluoroethyl trifluoromethanesulfonate (0.802 mL, 5.57 mmol) and DIEA (1.458 mL, 8.35 mmol) in DMF (20 mL) was heated to 50 °C for 24 h. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography (15percent EtO Ac/Hex). A clear oil corresponding to Cap L-23 step a (0.385 g) was isolated.XH NMR (400MHz, CDCI3) delta 3.71 (s, 3H), 3.55 (t, J=4.8 Hz, 1H), 3.22 - 3.03 (m, 3H), 2.71 (dt, J=l 1.2, 4.4 Hz, 1H), 1.98 (dq, J=13.3, 4.4 Hz, 1H), 1.87 - 1.77 (m, 1H), 1.64 - 1.48 (m, 3H), 1.33 - 1.23 (m, 1H);19F NMR (376MHz, CDCI3) delta -71.28 (s, 3F); 13C NMR (101MHz, CDCI3) delta 173.5, 125.7 (q, J=279.7 Hz, 1C), 62.8, 57.0 (q, J=30.8 Hz, 1C), 51.5, 50.3, 28.8, 25.5, 20.9.
  • 6
  • [ 6226-25-1 ]
  • [ 36138-76-8 ]
  • 4-bromo-1-methyl-2-(2,2,2-trifluoroethoxy)benzene [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Cooling with ice; To an ice-cooled sol. of <strong>[36138-76-8]5-bromo-2-methylphenol</strong> (1.87 g, 10 mmol) and Cs2C03 (4.23 g, 13 mmol) in DMF (20 mL) is added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.67 mL, 11 mmol). The mixture is stirred overnight while warming up to rt. The mixture is partitioned between water (100 mL) and EtOAc (100 mL). The layers are separated. The aq. phase is extracted with EtOAc (2 x 50 mL). The comb. org. layers are washed with water (3 x 100 mL) and brine (1x 100 mL), dried over MgS04, filtered, and the solvents are removed under reduced pressure to yield the crude title product. LC-MS: tR = 0.96 min (conditions 3).
  • 7
  • [ 6226-25-1 ]
  • [ 847818-70-6 ]
  • [ 1049730-42-8 ]
YieldReaction ConditionsOperation in experiment
13.16% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.8 mmol) in Nu,Nu-Dimethylformamide (DMF) (50 mL) and was added Cs2C03 (16.79 g, 51.5 mmol) at RT and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.45 mL, 30.9 mmol) added drop wise at RT.The reaction mixture was stirred at 100 C for 3 hr. The reaction mixture was diluted with water(100 mL) and extracted with EtOAc (2 X 100 mL), the combined organics were washed with cold water(3 X 100ml) and brine solution (100ml) and dried over Na2S04,filtered and evaporated under vacuo to get 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-lH-pyrazole (1.8 g, 3.39 mmol, 13.16 % yield) as an off white gummy liquid
  • 8
  • [ 96-81-1 ]
  • [ 6226-25-1 ]
  • C9H14F3NO3 [ No CAS ]
  • 9
  • [ 6226-25-1 ]
  • [ 7149-75-9 ]
  • (4-chloro-3-methylphenyl)-(2,2,2-trifluoroethyl)amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
209 mg With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 20h; Step 1 (0420) To a mixture of <strong>[7149-75-9]4-chloro-3-methylphenylamine</strong> (350 mg), potassium carbonate (1.09 g) and N,N-dimethylformamide (10 mL) was added trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (0.57 mL), and the mixture was stirred at an external temperature of 80° C. for 20 hours. The mixture was cooled to room temperature. After the mixture was diluted with ethyl acetate, and the resulting mixture was washed with water, saturated sodium hydrogen carbonate aqueous solution and brine successively, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 0percent-10percent ethyl acetate:hexane, gradient elution) to give (4-chloro-3-methylphenyl)-(2,2,2-trifluoroethyl)amine (209 mg). (0421) 1H-NMR (CDCl3) delta ppm: 2.31 (3H, s), 3.65-3.90 (3H, m), 6.46 (1H, dd, J=8.5, 2.8 Hz), 6.55 (1H, d, J=2.8 Hz), 7.15 (1H, d, J=8.5 Hz).
  • 10
  • [ 859518-32-4 ]
  • [ 6226-25-1 ]
  • tert-butyl (R)-2-phenyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With potassium carbonate; In acetonitrile; at 20.0℃; for 16.0h; To a solution of <strong>[859518-32-4]tert-butyl (R)-2-phenylpiperazine-1-carboxylate</strong> (0.30 g, 1.14 mmol) in acetonitrile (6.0 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.33 mL, 2.29 mmol) and potassium carbonate (0.32 g, 2.29 mmol). After stirring at ambient temperature for 16 h, the reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous layer was removed and the organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound as a colorless oil (0.389 g, 99% yield). MS (ES+) m/z 345.1 (M + 1). 1H NMR (300 MHz, CDCl3) δ 7.53-7.50 (m, 2H), 7.36-7.27 (m, 3H), 5.27-5.26 (m, 1H), 3.92-3.87 (m, 1H), 3.48-3.42 (m, 111), 3.06-2.96 (m, 3H), 2.90-2.8 1 (m, 2H), 2.58-2.50 (m, 1H), 1.48 (s, 9H); 19F NMR (282 MHz, CDCl3): δ -68.6 (s, 3F).
  • 11
  • [ 28466-26-4 ]
  • [ 6226-25-1 ]
  • N-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With potassium carbonate; triethylamine; In acetonitrile; at 20 - 90℃; To a solution of <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (300 mg, 95% purity, 3.43 mmol) in acetonitrile(17 mL)were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (741 p1, 5.1 mmol, CASRN 6226-25-1), powdered potassium carbonate (1.06 g, 7.65 mmol), and triethylamine(720 pL, 5.1 mmol). The mixture was heated to 90C for 4h and stirred at roomtemperature overnight. For work-up, it was filtered, and the solid was rinsed with ethylacetate. Concentraction of the filtrate in vacuo followed by flash chromatography led to the title compound (435 mg, 73% yield, 95% purity).LC-MS (Method A): Rt = 0.61 mm; MS (ESIpos): mlz = 166 (M+H)1HNMR (400MHz, DMSO-d6) oe [ppm]: 3.62 (qd, 2H), 5.06 (t, 1H), 7.13 (s, 2H), 12.12 (s,1H).
  • 12
  • [ 6226-25-1 ]
  • [ 2105-96-6 ]
  • 1-fluoro-2-nitro-4-(2,2,2-trifluoroethoxy)benzene [ No CAS ]
YieldReaction ConditionsOperation in experiment
70.3% With potassium carbonate; In N,N-dimethyl-formamide; at 160℃;Microwave irradiation; To a mixture of <strong>[2105-96-6]4-<strong>[2105-96-6]fluoro-3-nitrophenol</strong></strong> (1.00 g, 6.37 mmol) and K2CO3 (1.76 g, 12.7 mmol) in DMF (10.0 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.963 mL, 6.68 mmol). The resulting reaction mixture was heated to 160 °C under microwave irradiation for 30 min, after which TLC analysis (20percent EtOAc in Hex) showed completion. Reaction mixture was taken up in EtOAc, washed with H2O, brine (2x's), dried over MgS04, filtered and concentrated. Crude residue was purified by flash column chromatography: silica gel with a gradient of 3 - 15percent EtOAc in Hex to afford l-fluoro-2-nitro-4-(2,2,2-trifluoroethoxy)benzene (1.07 g, 70.3 percent yield) as a gold syrup, which solidified upon standing. NMR (400 MHz, DMSO-cfe) d 7.84 (dd, J= 5.9, 3.2 Hz, 1H), (0904) 7.61 (dd, J= 10.7, 9.2 Hz, 1H), 7.54 (ddd, J= 9.3, 3.8, 3.2 Hz, 1H), 4.92 (q, J= 8.8 Hz, 2H). 19F NMR (376 MHz, DMSO-ifc) d -72.57 (t, J= 8.7 Hz, 3F), -127.72 (ddd, J= 10.3, 5.8, 3.7 Hz, 1F). LCMS RT (Method 2) = 3.477 min.
  • 13
  • [ 6226-25-1 ]
  • [ 35344-95-7 ]
  • [ 790254-33-0 ]
YieldReaction ConditionsOperation in experiment
16.18% With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h; To the stirred solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> 8-1 (200 mg, 2.08 mmol) in DMF (5 mL) was added cesium carbonate (1.70 g, 5.20 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 8-2 (579.73 mg, 2.50 mmol, 360.08 uL). The reaction was heated at 60C for 16 hours and then quenched with cold water. The organic layer was extracted with ethyl acetate, washed with saturated aqueous solution of NaHCCb, dried over Na2S04and concentrated under reduced pressure to afford crude material that was purified by column chromatography to afford 1 -(2,2,2- triiluoroethyl)<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> 3 (60 mg, 336.87 urnol, 16.18% yield) as a gummy liquid. 1H NMR (400 MHz, DMSO-d6) d 9.85 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1 1 1 ), 5.27 (q, J = 18.12, 9.00Hz, 21 1 ).
  • 14
  • [ 6226-25-1 ]
  • [ 5497-76-7 ]
  • C11H18F3NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate; In acetonitrile; at 20℃; for 48h; <strong>[5497-76-7]tert-butyl (2S)-pyrrolidine-2-carboxylate hydrochloride</strong> (28) (1.26 g, 6.08 mmol, 1 eq.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (29) (2.82 g, 12.16 mmol, 2 eq) and potassium carbonate (2.5 g, 18.11 mmol, 3 eq) were mixed in acetonitrile (30 mL). The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was then filtered and evaporated. The residue was dissolved in ethyl acetate (100 mL) and the organic solution was washed with water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo affording sufficiently pure 30 (1.46 g, 85% yield).1H NMR (400 MHz, DMSO-d6) d 3.49- 3.34 (m, 3H), 3.11- 2.99 (m, 1H), 2.73 (dd, J = 15.2, 7.4 Hz, 1H), 2.07- 1.93 (m, 1H), 1.85- 1.70 (m, 3H), 1.40 (s, 9H).
 

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