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Chemical Structure| 1171331-39-7 Chemical Structure| 1171331-39-7

Structure of 1171331-39-7

Chemical Structure| 1171331-39-7

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Product Details of [ 1171331-39-7 ]

CAS No. :1171331-39-7
Formula : C4H8ClF3N2O
M.W : 192.57
SMILES Code : O=C(NCC(F)(F)F)CN.[H]Cl
MDL No. :MFCD12197070
InChI Key :DBNFKWRZLGVLSH-UHFFFAOYSA-N
Pubchem ID :42913698

Safety of [ 1171331-39-7 ]

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

Computational Chemistry of [ 1171331-39-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 0
Fraction Csp3 0.75
Num. rotatable bonds 4
Num. H-bond acceptors 5.0
Num. H-bond donors 2.0
Molar Refractivity 34.21
TPSA ?

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

55.12 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

0.55
Log Po/w (WLOGP)?

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

1.69
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.

0.17
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

0.27
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.53

Water Solubility

Log S (ESOL):?

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

-1.12
Solubility 14.7 mg/ml ; 0.0765 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.28
Solubility 10.1 mg/ml ; 0.0525 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very 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

-1.2
Solubility 12.1 mg/ml ; 0.0627 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.

-7.08 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)

1.36

Application In Synthesis of [ 1171331-39-7 ]

* 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 [ 1171331-39-7 ]

[ 1171331-39-7 ] Synthesis Path-Downstream   1~22

  • 1
  • [ 1171331-39-7 ]
  • [ 191406-82-3 ]
  • (6S,7R,10S)-7-Isobutyl-8-oxo-2-oxa-9-aza-bicyclo[10.2.2]hexadeca-1(15),12(16),13-triene-6,10-dicarboxylic acid 6-(benzyloxy-amide) 10-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide} [ No CAS ]
  • 2
  • [ 1233036-64-0 ]
  • [ 1171331-39-7 ]
  • [ 1233232-77-3 ]
YieldReaction ConditionsOperation in experiment
52% Step 4: Synthesis of 2-({2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3-yl]-N-hydroxy-benzimidoyl}-amino)-N-(2,2,2-trifluoro-ethyl)- acetamideTo a solution of 2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro- isoxazol-3-yl]-benzaldehyde oxime (i.e. the product of Step 3, 250 mg) in DMF (5 mL) was added N-chloro succinimide (80 mg) and heated to 75C for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SU4) and concentrated in vacuo to % of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of (2,2,2-trifluoro-ethylcarbamoyl)-methyl-ammoniumchloride (1 10 mg) and triethylamine (0.29 mL, 0.21 g) in THF (10 mL) and stirred at room tempera- ture over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (176 mg, 52%).Characterization by HPLC-MS: 3.848 min, M = 591.00
  • 3
  • [ 1231755-15-9 ]
  • [ 1171331-39-7 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; In methanol; at 20℃; for 12h; 2-/V-(te/f-Butoxycarbonyl)-1 -oxo-1-N-(2,2,2-trifluoroethyl)-1 ,2-diaminoethane (1 eq) was dissolved in 2M HCI/MeOH and stirred for 12 h at room temperature. The reaction mixture was concentrated under reduced pressure till dryness to afford the title compound in quantitative yield.
66% With hydrogenchloride; In ethyl acetate; at 18 - 35.5℃;Product distribution / selectivity; A portion of the product of Example 2, Step A (11.7 g) was diluted with ethyl acetate (50 mL) and treated with hydrogen chloride gas at 18-35.5 C until the starting material was consumed. The resulting slurry was cooled to 0-5 C, stirred for approximately 1 hour at that temperature, and then filtered. The residue was washed twice with ethyl acetate (20 ml each) and dried in a vacuum oven at 60C to give the title compound as a white solid (7.22 g, 66% yield).1H NMR (DMSO-d6): 9.24 (tr, / = 6.2 Hz, 1H), 8.3 (s, 3H), 4.11-3.89 (m, 2H), 3.64 (s, 2H), 1.21-1.50 ppm (s, 9H); 19F-NMR (DMSO-d6): -70.69 ppm (tr, / = 10.1Hz).
2.4 g With hydrogenchloride; In 1,4-dioxane; at 0 - 24℃; for 10h; Example 95 Preparation of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (C350) To a stirred solution of tert-butyl (2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)carbamate (C362; 3 g, 15.6 mmol) in dioxane (20 mL) was added 4 M HCl in dioxane (23 mL, 93.8 mmol) dropwise at 0 C., and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure. The title compound was isolated as an off-white solid (2.4 g), which was used without purification: 1H NMR (300 MHz, DMSO-d6) delta 9.17-9.13 (m, 1H), 8.21 (br s, 3H), 4.07-3.95 (m, 2H), 3.67-3.64 (m, 2H).
  • 4
  • [ 1371632-80-2 ]
  • [ 1171331-39-7 ]
YieldReaction ConditionsOperation in experiment
A portion of the product of Example 7, Step B (12.0 g) was dissolved in methanol (300 mL) and added to a pressure reactor (Parr model 4540, 600 mL, Hasteloy C) along with 5% palladium on carbon (0.6 g) catalyst. The reactor was flushed with nitrogen and then with hydrogen, and heated to 70 C under 100 psi of hydrogen pressure until the hydrogen uptake ceased (3 hr). The reactor was cooled and flushed with nitrogen, then the crude reaction product was filtered through a bed a Celite filter aid to remove the catalyst and the cake washed with methanol. The solvent and toluene by-product were removed by distillation, leaving an amber oil (5.45 g, 89% product by GC).The crude oil product from two runs of the above hydrogenolysis (10.9 g total) was diluted with ethyl acetate (50 mL) and treated with hydrogen chloride gas at ambient temperature until the starting material was consumed. The resulting slurry was filtered and the solid was washed with ethyl acetate (20 mL) and dried on the filter under a blanket of nitrogen to give the title compound as a white solid (10.0 g)..H NMR (DMSO-d6): 9.24 (tr, / = 6.2 Hz, 1H), 8.3 (s, 3H), 4.11-3.89 (m, 2H), 3.64 (s, 2H); 19F-NMR (DMSO-d6): -70.69 ppm (tr, / = 10.1Hz).
  • 5
  • [ 1371632-79-9 ]
  • [ 1171331-39-7 ]
YieldReaction ConditionsOperation in experiment
10% Palladium on carbon (1.00 g) was added to the combined wash and filtrate and placed under a hydrogen atmosphere (ballon). After approximately 2 hours, the reaction slurry was heated to 50 C and hydrogenated for approximately 4 hours. The reaction mixture was placed under a nitrogen atmosphere, cooled to room temperature and then filtered through a Celite pad (15 g) wetted with wo-propyl acetate. The residue was rinsed with iio-propyl acetate (30 mL). The combined filtrate and rinse was treated with hydrogen chloride gas until the pH of the mixture was 1-2 by pH indicator paper, then nitrogen was bubbled through the slurry at 30-35 C until the pH was 4-6 by pH indicator paper. The slurry was cooled to <5 C and filtered. The residue was rinsed with wo-propyl acetate (20 mL) and dried in a vacuum oven at 60 C to give the title compound as a gray solid (7.75 g, 84% yield).
  • 6
  • [ 1414378-26-9 ]
  • [ 1171331-39-7 ]
  • [ 1414378-58-7 ]
YieldReaction ConditionsOperation in experiment
84.6% With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h; Example 2423-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-ox o-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxa mideStir a mixture of3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid (1.0 g, 2.14 mmol), N,N-diisopropylethylamine (827 mg, 6.41 mmol),2-amino-N-(2,2,2-trifluoroethyl) acetamide hydrochloride (658 mg, 2.56 mmol) and HATU (1.2 g, 3.2 mmol) in (¾(¾ (10 mL) at room temperature for 2 hours. The reaction mixture is diluted with CH2CI2 (50 mL) and is washed with water (10 mLx 3) and brine. Then the organic layer is dried over anhydrous Na2S04 and is concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro- 4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluor oethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide as a white solid (1.1 g, 84.6 %). MS (m/z): 606.0 (M+l).
  • 7
  • [ 1416979-93-5 ]
  • [ 1171331-39-7 ]
  • [ 1416977-61-1 ]
YieldReaction ConditionsOperation in experiment
41% To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 C. oil bath for 1.5 h, treated with <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61 C.: 1H NMR (400 MHz, CDCl3) delta 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta -69.31, -72.3; EIMS m/z 626.9 ([M+1]+).
41% To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added carbonyldiimidazole (82 mg, 0.51 mmol). The mixture was heated in a 50 C. oil bath for 1.5 h, treated with <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2*) and once with sat. NaCl (1*). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61 C.: 1H NMR (400 MHz, CDCl3) delta 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta -69.31, -72.3; EIMS m/z 626.9 ([M+1]+).
41% Example 108 : Preparation of (Z)-2-Bromo- V-(2-oxo-2-((2,2,2- trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l-en-l- yl)benzamide (AC95)To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-l- en-l-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 C oil bath for 1.5 h, treated with 2-amino- N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, .057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et20 and washed twice with aq. 5% NaHS04 (2X) and once with sat. NaCl (IX). After dying over MgS04, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61C: ]H NMR (400 MHz, CDC13) delta 7.58 (d, 7 = 7.9 Hz, 1H), 7.44 - 7.29 (m, 3H), 7.14 (dd, 7 = 7.9, 1.6 Hz, 1H), 6.86 (d, 7 = 11.4 Hz, 1H), 6.76 (t, / = 5.9 Hz, 1H), 6.59 (br s, 1H), 6.21 - 6.04 (m, 1H), 4.23 (d, / = 5.5 Hz, 1H), 3.98 (qd, / = 9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDC13) delta -69.31, -72.3; EIMS m/z 626.9 ([M+l]+).
41% To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 C oil bath for 1.5 h, treated with 2-amino- N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, .057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et20 and washed twice with aq. 5% NaHS04 (2X) and once with sat. NaCl (IX). After dying over MgS04, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61C: 1H NMR (400 MHz, CDC13) delta 7.58 (d, 7 = 7.9 Hz, 1H), 7.44 - 7.29 (m, 3H), 7.14 (dd, 7 = 7.9, 1.6 Hz, 1H), 6.86 (d, 7 = 11.4 Hz, 1H), 6.76 (t, / = 5.9 Hz, 1H), 6.59 (br s, 1H), 6.21 - 6.04 (m, 1H), 4.23 (d, / = 5.5 Hz, 1H), 3.98 (qd, / = 9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDC13) delta -69.31, -72.3; EIMS m/z 626.9 ([M+l]+).
41% Example 108 Preparation of (Z)-2-Bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC95) To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 C. oil bath for 1.5 h, treated with <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61 C.: 1H NMR (400 MHz, CDCl3) delta 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta -69.31, -72.3; EIMS m/z 626.9 ([M+1]+).
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; diethyl ether; Example 108 Preparation of (Z)-2-Bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC95) To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added carbonyldiimidazole (82 mg, 0.51 mmol). The mixture was heated in a 50 C. oil bath for 1.5 h, treated with <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aqueous 5% sodium bisulfate (NaHSO4) (2*) and once with saturated NaCl (1*). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61 C.: 1H NMR (400 MHz, CDCl3) delta 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta -69.31, -72.3; EIMS m/z 626.9 ([M+1]+).

  • 8
  • [ 1416979-92-4 ]
  • [ 1171331-39-7 ]
  • [ 1416977-61-1 ]
YieldReaction ConditionsOperation in experiment
41% for 8h;Reflux; Example 108Preparation of (Z)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC95); To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 C. oil bath for 1.5 h, treated with <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61 C.: 1H NMR (400 MHz, CDCl3) delta 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta -69.31, -72.3; EIMS m/z 626.9 ([M+1]+).
  • 9
  • [ 1427274-51-8 ]
  • [ 1171331-39-7 ]
  • [ 1427273-67-3 ]
YieldReaction ConditionsOperation in experiment
84% With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20 - 25℃; for 16h; To a solution of the product of step 1 (2.2 g), <strong>[1171331-39-7][2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]ammonium chloride</strong> (1.22 g) and bromotripyrrolidinophospho25 nium hexafluorophosphate (uPyBroPu, 2.95 g) in CH2CI2 (100 mL) at room temperaturewas added N,N-diisopropylethylamine (3.53 mL). The reaction was stirred at room temperature for 16 h, then concentrated and redissolved in ethyl acetate (200 mL). The organic layer was washed with 5% aqueous HCI (2x) and 5% aqueous K2C03 (2x), dried (Na2504), filtered, and concentrated to afford a residue that was purified by flashchromatography on silica gel (ethyl acetate/cyclohexane). The product was obtained as amorphous white foam (2.45 g, 84%).
  • 10
  • C18H10Cl3F4NOS [ No CAS ]
  • [ 1171331-39-7 ]
  • [ 1444176-77-5 ]
YieldReaction ConditionsOperation in experiment
40% With triethylamine; In tetrahydrofuran; To a solution of the product of step 2 (0.25 g) in tolueneCH2CI2 (1:1, 20 mL) was added N,N-dimethylformamide (?DMF?, 1 drop) and oxalyl chloride (0.14 mL). The reaction was stirred overnight, concentrated, and azeotroped with CH2CI2 (5x). The obtained residue (0.26 g) was dissolved in THF (30 mL) and added to a solution of 2-amino-N- (2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine (0.22 g) in THF (30 mL).The reaction was stirred overnight, filtered and concentrated to afford a residue that was purified by flash chromatography on silica gel (ethyl acetatecyclohexane). The product was obtained as amorphous foam (0.13 g, 40%). HPLC-MS (method B): 1.364 mi M = 590.2.
  • 11
  • [ 1312697-82-7 ]
  • [ 1171331-39-7 ]
  • [ 1312697-19-0 ]
YieldReaction ConditionsOperation in experiment
21 mg With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h; To a solution of 28 (40 mg, 0.09 mmol), HATU (51 mg, 0.135 mmol) and Et3N (0.04 mL, 0.27 mmol) in DMF (5 mL) was added crude compound <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (80 mg). The mixture was stirred at rt overnight. EA (40 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the final compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluo-roethylamino)ethyl)indolizine-8-carboxamide(4, 21 mg; yield 40%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 8.86 (t, J = 6.0 Hz, 1H), 8.69 (t, J = 6.0 Hz, 1H), 8.55 (s, 1H), 7.84 (s,1H), 7.69 (s, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.28 (d, J =7.6 Hz, 1H), 7.18 (d, J = 3.2 Hz, 1H), 7.06 (t, J =3.2 Hz, 1H), 4.64 (d, J = 18.0 Hz, 1H), 4.53 (d, J = 18.0 Hz, 1H), 4.01-3.94 (m, 4H) ppm;HPLC purity: 95.4% at 220 nm and 95.6% at 254 nm; MS (ESI+): m/z = 581.0 (M+1,the observed isotope pattern consistent with the theoretical chemical formula C23H16Cl2F6N4O3).
  • 12
  • C16H9Cl3F3NO3S*C9H13N [ No CAS ]
  • [ 1171331-39-7 ]
  • [ 1369852-71-0 ]
YieldReaction ConditionsOperation in experiment
Example 4: Preparation of an (S)-enantiomer of formula (I) from an(S)-isoxazoline thiophene carboxylic acid salt(i) 15 kg of the (S)-isoxazoline thiophene carboxylic acid salt from Example 2 in 150 kg of toluene are heated to 60C. the solution is extracted three times with 56 kg of imolar HCI solution. About 50% of the organic layer is then distilled off under vacuum. Following the addition of further 60 kg of toluene the mixture is heated to 110C and 8 kg of thionyl chloride are dosed slowly to the reaction mixture. Following stirring for an additional hour 94 kg of toluene are removed under vacuum. The reaction mixture is cooled to ambient temperature, and 94 kg of dichloromethane are added.(ii) The dichloromethane solution of step (i) is added to a mixture of 5.1 kg 2-amino-2?,2?,2?- trifluoroethyl-acetamide hydrochloride and 9.8 kg of triethylamine in 93 kg of dichloromethane at 5C. The reaction mixture is stirred for additional 5 hours and is then extracted with 4% hydrochloric acid, 8% sodium hydrogen carbonate and water. Most of the organic layer is then removed under vacuum, and 50 kg of toluene are added. The reaction mixture is kept at 40C, and 290 kg of heptane are added slowly to precipitate the product. The suspension obtained is cooled to below 5C, and the crude product is isolated by filtration and is washed with 25 kg of heptane. Crystallization of the product may be performed as appropriate.
  • 13
  • N-(6-(5-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide [ No CAS ]
  • [ 1171331-39-7 ]
  • 2-(3-(6-(5-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)ureido)-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]
  • 14
  • 10-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-9-anthracenecarboxylic acid [ No CAS ]
  • [ 1171331-39-7 ]
  • 10-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-9-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)anthraceamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 8h; A/,A/-Diisopropylethylamine (1 eq) was added dropwise to a 0 C stirring solution of 10- (4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1 ,2-oxazol-3-yl)-9- anthracenecarboxylic acid (1 eq), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDCI, 1 eq) and A/,A/-dimethylaminopyridine (0.1 eq) in dry DCM. The reaction mixture was then stirred at room temperature for 8 h and was quenched with 1 % HCI. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography using Hex/EtOAc gradient (90%->50%) afforded the title compound in 71 %. MS confirmed.
  • 15
  • 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4-yl]indane-4-carboxylic acid [ No CAS ]
  • [ 1171331-39-7 ]
  • 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]indane-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; To a solution of the product of step 5 (0.25 g), 2-amino-N-(2,2,2- trifluoroethyl)acetamide hydrochloride (0.1 g, CAS 1 171331 -39-7) and bromotripyrrolidinophosphonium hexafluorophosphate ("PyBroP", 0.24 g) in CH2CI2 (40 mL) at r.t. was added N,N-diisopropylethylamine (0.18 g). The reaction was stirred at r.t. overnight. Then, the reaction was quenched with water. The layers were separated, and the organic layer was dried (Na2S04), filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to afford the product (0.17 g, 65%). H NMR (400 MHz, CDCI3): delta 7.5 (d, 1 H), 7.45-7.40 (m, 3H), 7.40-7.35 (m, 1 H), 7.1 (d, 1 H), 6.9 (m, 1 H), 6.4 (s, 1 H), 4.25 (d, 2H), 4.0-3.9 (m, 2H), 3.85 (d, 1 H), 3.7 (d, 1 H), 3.2 (m, 2H), 3.0 (m, 2H), 2.2-2.05 (m, 2H)
  • 16
  • 2-amino-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]
  • [ 1171331-39-7 ]
YieldReaction ConditionsOperation in experiment
55 g With hydrogenchloride; In diethyl ether; at 10 - 20℃; In a 1 L four-necked flask, 50 g of 2-amino-N- (2,2,2-trifluoroethyl) acetoamide and 500 ml of diethyl ether were added and dissolved, and the mixture was cooled to 10 C. Hydrogen chloride gas was bubbled for 30 minutes while stirring. During bubbling, the temperature was kept between 10 and 20 C. 200 ml of diethyl ether was added and the excess hydrogen chloride gas was removed by bubbling with nitrogen gas for 10 minutes, followed by filtration and drying under reduced pressure to obtain 55 g of a white solid
  • 17
  • (Z)-4-(1,4,4,4-tetra-fluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid [ No CAS ]
  • [ 128625-52-5 ]
  • [ 1171331-39-7 ]
  • (Z)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; Example 13 Preparation of (Z)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F1) To a 25 mL vial was added (Z)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C2) (0.105 g, 0.210 mmol) and dichloromethane (4 mL) to give a yellow solution. 2-Amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (0.0610 g, 0.320 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.165 g, 0.320 mmol) were then added. Triethylamine (0.120 mL, 0.850 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and purified by flash column chromatography providing the title compound as a yellow gum (0.105 g, 74%). The following compounds were prepared according to the procedures disclosed in Example 13:
  • 18
  • 4-[2-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]ethenyl]naphthalene-1-carboxylic acid [ No CAS ]
  • [ 1171331-39-7 ]
  • 2-([4-[2-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]ethenyl]naphthalen-1-yl]formamido)-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% With N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; at 20℃; for 2h; Into a 50-mL round-bottom flask, was placed N,N-dimethylformamide (4 mL), 4- [2- [5 -[3- chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-l,2-oxazol-3- yl]ethenyl]naphthalene-l-carboxylic acid (7-2, 60 mg, 0.12 mmol, 1.00 equiv), 2-amino-N- (2,2,2-trifluoroethyl)acetamide hydrochloride (7-3, 30 mg, 0.19 mmol, 1.65 equiv), HATU (80 mg, 0.21 mmol, 1.80 equiv) and DIEA (50 mg, 0.39 mmol, 3.31 equiv). The resulting solution was stirred for 2 h at room temperature. The crude product was purified by Flash- Prep-HPLC with the following conditions (IntelFlash-1): Column, CI 8 silica gel; mobile phase, H20 and CH3CN (20% CH3CN increasing to 80% within 25 min); Detector, UV 254 nm. This resulted in 31.3 mg (41%) of 2-([4-[2-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4,5-dihy dro- 1 ,2-oxazol-3-yl] ethenyl]naphthalen- 1 -yl]formamido)-N-(2,2,2- trifluoroethyl)acetarnide (Compound 1) as a white solid. (ES, m/z): 652 [M+H]+; ^-NMR (300 MHz, CDC , ppm) delta 8.38-8.35 (m, 1H), 8.15-8.12 (m, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.80-7.55 (m, 6H), 7.15 (d, J=15.9 Hz, 1H), 6.79 (br, 1H), 6.66 (br, 1H), 4.35-4.30 (m, 2H), 4.15 (d, J=16.8 Hz, 1H), 4.07-3.96 (m, 2H), 3.73 (d, J=16.5 Hz, 1H); 19F-NMR (300 MHz, CDC , ppm): delta -62.8, -72.4, -79.5.
  • 19
  • 2,6-dimethyl-4-[5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]benzoic acid [ No CAS ]
  • [ 1171331-39-7 ]
  • 2-[(2,6-dimethyl-4-[5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]phenyl)formamido]-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
29% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 8h; Into a 50- mL round-bottom flask were placed 2,6-dimethyl-4-[5-[l-methyl-3-(trifluoromethyl)-lH- pyrazol-5-yl]-5-(trifluoromethyl)-4,5-dihydro-l,2-oxazol-3-yl]benzoic acid (65 mg, 0.15 mmol, 1.00 equiv), <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (30 mg, 0.19 mmol, 1.20 equiv), HATU (116 mg, 0.3 mmol, 2.00 equiv), DIEA (57.8 mg, 0.45 mmol, 3.00 equiv) and N,N-dimethylformamide (8 mL). The resulting solution was stirred for 8 h at room temperature. The resulting solution was diluted with 30 mL of EA and washed with 3x20 mL of H20. The organic layer was concentrated under vacuum and the crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H20 and CH3CN (10% CH3CN increasing to 70% within 15 min); Detector, UV 220 nm. This resulted in 25.2 mg (29%) of 2-[(2,6-dimethyl-4-[5-[l-methyl-3-(trifluoromethyl)-lH-pyrazol-5- yl]-5-(trifluoromethyl)-4,5-dihydro-l,2-oxazol-3-yl]phenyl)formamido]-N-(2,2,2- trifluoroethyl)acetamide as a white solid. (ES, w/z):573[M+H]+; 1H MR (300 MHz, CDC13, ppm) delta 7.36 (s, 2H), 6.91 (s, 1H), 6.56 (brs, 1H), 6.37 (brs, 1H), 4.19-4.08 (m, 6H), 3.99-3.96 (m, 2H), 3.93-3.81 (m, 1H), 2.35 (s, 6H).
  • 20
  • [ 201230-82-2 ]
  • 3-(3-bromo-4-chlorophenyl)-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole [ No CAS ]
  • [ 1171331-39-7 ]
  • 2-[(2-chloro-5-[5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]phenyl)formamido]-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.097% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium acetate; In 1,4-dioxane; at 120℃; under 3800.26 Torr; for 4h; Into a 50-mL pressure tank reactor were placed 3-(3-bromo-4-chlorophenyl)-5-[l-methyl-3-(trifluoromethyl)- lH-pyrazol-4-yl]-5-(trifluoromethyl)-4,5-dihydro-l,2-oxazole (200 mg, 0.42 mmol, 1.00 equiv), <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (323 mg, 1.68 mmol, 4.00 equiv), Pd(dppf)Cl2 (93 mg, 0.13 mmol, 0.30 equiv), CH3COONa (104 mg, 1.27 mmol, 3.02 equiv) and dioxane (15 mL). To this mixture was introduced CO (5 atm) and the resulting solution was stirred for 4 h at 120C. The solids were filtered out. The filtrate was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H20 and CH3CN (33% CH3CN increasing to 83% within 30 min; Detector, UV 254 nm, 220 nm. This resulted in 27 mg (11.097%) of 2- [(2-chloro-5-[5-[l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-yl]-5-(trifluoromethyl)-4,5-dihydro- l,2-oxazol-3-yl]phenyl)formamido]-N-(2,2,2-trifluoroethyl)acetamide as a white solid. MS (ESI, /// r): 580 [M+H]+; 1H MR (300 MHz, CDC , ppm) delta: 7.92 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.13 (s, 1H), 6.64 (s, 1H), 4.27 (br, 2H), 4.05-4.01 (m, 6H), 3.73 (d, J= 17.2 Hz, 1H).
  • 21
  • [ 201230-82-2 ]
  • 3-(3-bromo-4-methylphenyl)-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole [ No CAS ]
  • [ 1171331-39-7 ]
  • 2-[(2-methyl-5-[5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]phenyl)formamido]-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; In 1,4-dioxane; at 120℃; under 3800.26 Torr; for 4h; Into a 50-mL pressure tank reactor were placed 3-(3-bromo-4-methylphenyl)-5-[l-methyl-3-(trifluoromethyl)- lH-pyrazol-4-yl]-5-(trifluoromethyl)-4,5-dihydro-l,2-oxazole (200 mg, 0.44 mmol, 1.00 equiv), <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (338 mg, 1.76 mmol, 4.00 equiv), Pd(dppf)Cl2 (32 mg, 0.04 mmol, 0.10 equiv), AcONa (108 mg, 1.32 mmol, 3.00 equiv) and dioxane (15 mL). To this solution CO (5atm) was introduced. The resulting solution was stirred for 4 h at 120C after which the solids were filtered out. The filtrate was concentrated under vacuum and the crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H20/CH3CN=5: 1 increasing to H20/CH3CN=1 :5 within 30 min; Detector, UV 254, 220 nm. This resulted in 75.9 mg (31%) of 2-[(2-methyl-5-[5-[l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-yl]-5-(trifluoromethyl)-4,5- dihydro-l,2-oxazol-3-yl]phenyl)formamido]-N-(2,2,2-trifluoroethyl)acetamide as a white solid. MS (ESI, /// r): 560 [M+H]+; 1H MR (300 MHz, COC3, ppm) delta: 7.76 (br, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 6.74 (brs, 1H), 6.68 (brs, 1H), 4.22 (br, 2H), 4.00 (br, 6H), 3.76-3.71 (m, 1H), 2.51 (s, 3H).
  • 22
  • 2-methyl-4-[5-(trifluoromethyl)-5-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-4,5-dihydro-1,2-oxazol-3-yl]benzoic acid [ No CAS ]
  • [ 1171331-39-7 ]
  • 2-([2-methyl-4-[5-(trifluoromethyl)-5-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-4,5-dihydro-1,2-oxazol-3-yl]phenyl]formamido)-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% Into a 50-mL (0728) 3- necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, were placed 2-methyl-4-[5-(trifluoromethyl)-5-[3-(trifluoromethyl)-lH-pyrazol-5-yl]- 4,5-dihydro-l,2-oxazol-3-yl]benzoic acid (80 mg, 0.20 mmol, 1.00 equiv), dichloromethane (10 mL) and HATU (89 mg, 0.23 mmol, 1.20 equiv), and the resulting solution was stirred for 0.5 h at room temperature. To this was added a solution of <strong>[1171331-39-7]2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride</strong> (61.3 mg, 0.32 mmol, 2.00 equiv) in dichloromethane (10 mL), DIEA (101.1 mg, 0.78 mmol, 4.00 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was washed with 1x20 mL of H20. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H20 and CH3CN (30% CH3CN increasing to 80% within 10 min); Detector, UV 254 nm. This resulted in 22.8 mg (22%) of 2-([2-methyl-4-[5-(trifluoromethyl)-5-[3- (trifluoromethyl)-lH-pyrazol-5-yl]-4,5-dihydro-l,2-oxazol-3-yl]phenyl]formamido)-N-(2,2,2- trifluoroethyl)acetamide as a white solid. MS (ESI, m/z): 545 [M+H]+; 1H MR (300 MHz, OMSO-d6, ppm) delta 8.68-8.58 (m, 2H), 7.64-7.62 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 4.46 (d, J= 18.1 Hz, 1H), 4.29 (d, J= 18.3 Hz, 1H), 4.11-3.88 (m, 4H), 2.41 (s, 3H).
 

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