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Chemical Structure| 372-31-6 Chemical Structure| 372-31-6
Chemical Structure| 372-31-6

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CAS No.: 372-31-6

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Product Details of [ 372-31-6 ]

CAS No. :372-31-6
Formula : C6H7F3O3
Linear Structure Formula :(CF3)C(O)CH2COOC2H5
M.W : 184.11
MDL No. :MFCD00000424
InChI Key :OCJKUQIPRNZDTK-UHFFFAOYSA-N
Pubchem ID :67793

Safety of [ 372-31-6 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H302-H412
Precautionary Statements:P210-P273-P301+P312+P330
Class:3
UN#:3272
Packing Group:Ⅲ

Calculated chemistry of [ 372-31-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 0
Fraction Csp3 0.67
Num. rotatable bonds 5
Num. H-bond acceptors 6.0
Num. H-bond donors 0.0
Molar Refractivity 32.63
TPSA ?

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

43.37 ?2

Lipophilicity

Log Po/w (iLOGP)?

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

1.65
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

1.37
Log Po/w (WLOGP)?

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

2.33
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.

0.81
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

1.6
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.55

Water Solubility

Log S (ESOL):?

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

-1.51
Solubility 5.63 mg/ml ; 0.0306 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.

-1.88
Solubility 2.41 mg/ml ; 0.0131 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

-1.6
Solubility 4.6 mg/ml ; 0.025 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.

-6.45 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

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

 No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

 1.77

Application In Synthesis [ 372-31-6 ]

* 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 [ 372-31-6 ]

[ 372-31-6 ] Synthesis Path-Downstream   1~24

  • 1
  • [ 6099-90-7 ]
  • [ 372-31-6 ]
  • [ 82747-44-2 ]
  • 2
  • [ 10133-22-9 ]
  • [ 372-31-6 ]
  • 2-Benzo[b]thiophen-5-ylmethyl-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester [ No CAS ]
  • 3
  • [ 372-31-6 ]
  • [ 53967-21-8 ]
  • ethyl 6-quinoxolinyl-α-(trifluoroacetyl)propanoate [ No CAS ]
  • 4
  • [ 58196-33-1 ]
  • [ 372-31-6 ]
  • [ 53518-16-4 ]
  • 5
  • [ 62-53-3 ]
  • [ 372-31-6 ]
  • [ 25199-84-2 ]
YieldReaction ConditionsOperation in experiment
46.5% A mixture of aniline (9.30 g, 100 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (36.8 g, 200 mmol) was stirred at 110 C for 1 hour. The reaction mixture was concentrated under reduced pressure, and then diluted with water (20 mL). Conc. H2S04 (110 g, 1.13 mol) was added carefully and the mixture stirred at 90C forhour, then cooled to room temperature and poured into ice water (500 mL). The precipitate was collected by filtration, and then recrystallised from ethanol (50 mL) to give the title compound (9.90 g, 46.5% yield) as a white solid. ?H NMR (400 MHz, DMSO-d6): 12.34 (bs, 1H), 7.75 (m, 2H), 7.45 (d, 1H), 7.32 (m, 1H), 6.99 (s, 1H). MS mlz 214.20 [M+Hjt
General Procedure 98: 4-Trifluoromethyl-1H-quinolin-2-one (Intermediate 465)Aniline (7.0 g, 75.3 mmol) and trifluoro ethylacetoacetate (15.4 ml, 105 mmol) were heated at 110 C. for 45 min. The excess ester was removed in vacuo. 75% H2SO4 was added and the mixture was heated at 90 C. for 45 min. After cooling, the mixture was poured onto ice and the resulting precipitate was collected by filtration to give title compound (7.0 g, 44%) which was used in the next step without further purification.MW: 212.15HPLCMS (Method C): [m/z]: 214
With triethylamine; In toluene;Heating / reflux; To a solution of the ester (5.46 mmol) and triethylamine (101 g, 10.86 mmol) in toluene (5 mL) was added a solution of aniline (6.52 mmol) in toluene (2 mL) at room temperature. The reaction mixture was refluxed until the reaction was complete. After workup, compound 56 was obtained, which was pure enough to be used in the next step.
  • 6
  • [ 100-63-0 ]
  • [ 372-31-6 ]
  • [ 96145-98-1 ]
YieldReaction ConditionsOperation in experiment
98.0% With acetic acid; at 10 - 80℃; for 6.5h; (Reference Example 2) Synthesis of 5-hydroxy-1-phenyl-3-trifluoromethylpyrazole: Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 12.0 g (0.2 mol) of acetic acid. The resulting solution was cooled to 10C or less with stirring, and 11.8 g (0.11 mol) of phenylhydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at 80C for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water was added thereto. The produced crystal was collected by filtration, washed twice with 50 mL of water and dried by a hot air drier to obtain 22.3 g (yield: 98.0%) of the title compound as a pale yellow crystal. LC-MS(EI): m/z=228 (M+), melting point: 190-192C.
92% In ethanol; for 12h;Reflux; Ethyl 4, 4, 4-1rifluoro3-oxobutanoate (S3, 200 p1., 1.37 mmoi, I equiv) and phenyihydrazine (148 IrL. 1.37 inmol, 1.00 equiv) were dissolved in ethanol (1.4 mL) and the resulting mixture was stirred for 12 hours at reflux. The reaction mixture was cooled to 24 c and the solvent was evaporated in vacuo. The residue was dissolved into ethyl acetate (3 mL) and washed with IN HCI (3 x 3 mL). The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The resulting material was washed with dichloromn ethane (5 mL) to afford the compound as orange solid (289 mg, 92%).Rf 0.25 (30% ethyl acetate-hexanes; UV). ?HNMR (500 MHz, DMSOd6): d 7.71 (d, 2H, H2, J = 8.0 Hz), 7.51 (dd, 2H, J = 8.0 Hz, H3), 7.38 (t, IH, J = 8.0 Hz, H4), 5.94 (s, 1Ff, H,). ?3C NMR (125 MHz, DMSOd6): oe 153.7 (C), 140.4 (q, 2JCF 37.4 Hz, C), 137.7 (C), 129.1 (CH), 127.2 (CH), 122.3 (CH), 121.3 (q, IJCF 266.9Hz, CF3), 85.6 (q, 3JCF =1.6 Hz, CH). ?9F NMR (375 MHz, DMS&-do): 61.8. IR (ATR.FTIR), cm?1: 3373 (br),1599 (in), 1505 (in), 1491 (m), 1456 (m), 1407(m), 1151 (s), 1119 (s), 984 (s), 758 (s), 691(s). HRMSESI (m/z): [M+H1 calculated for C10H8F3N50, 229.0583; found, 229.0598.
87.9% With hydrogenchloride; In ethanol; water; for 1h;Heating / reflux; 20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals. 1H-NMR [CDCl3/TMS, delta (ppm) ]: 7.68-7.41 (5H,m), 5.86 (1H,s), 3.71 (1H,s)
87.9% With hydrogenchloride; In ethanol; for 1h;Heating / reflux; REFERENCE EXAMPLE 9 Production of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol; 20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals. 1H-NMR [CDCl3/TMS, delta (ppm)]: 7.68-7.41 (5H,m), 5.86 (1H,s), 3.71 (1H,s)
72% With acetic acid; at 110℃; Phenylhydrazine (433 mg, 4 mmol) and ethyl 4,4,4-trifluoroacetoacetate(736 mg, 4 mmol) were dissolved in glacial aceticacid. The reaction mixture was stirred at 110 C until TLC (hexane/EtOAc 1:1) showed complete consumption of the startingmaterial. Upon cooling a white solid precipitated from the solutionand was filtered and washed with ice-cold ethanol. Purification byflash column chromatography afforded the title compound as awhite solid (652 mg, 2.86 mmol, 72%). 1H NMR (400 MHz, DMSOd6,ppm) d: 5.94 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz,2H), 7.71 (d, J = 8.0 Hz, 2H), 12.49 (s, 1H) ppm; 13C NMR (100MHz, DMSO-d6, ppm) d: 85.6, 121.3 (q, 1JCF = 267 Hz), 122.3,127.2, 129.1, 137.7, 140.4 (d, 2JCF = 37 Hz), 153.7 ppm.
71.8% With acetic acid; at 10 - 80℃; for 6.5h; (Reference Example 2) Synthesis of 5-hydroxy-1-phenyl-3-trifluoromethylpyrazole 18.4 g (0.1 mole) of ethyl 4,4,4-trifluoroacetoacetate was dissolved in 12.0 g (0.2 mole) of acetic acid. The solution was cooled to 10C or lower with stirring. Thereto was dropwise added, in 0.5 hour, 11.8 g (0.11 mole) of phenylhydrazine. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and successively at 80C for 5 hours to give rise to a reaction. After the reaction, the mixture was cooled to room temperature. Thereto were added 100 ml of water. The resulting crystals were collected by filtration, washed with 50 ml of water twice, and dried in a hot-air drier, to obtain 22.3 g (yield: 98.0%) of a title compound as light yellow crystals.
67% With toluene-4-sulfonic acid; In ethanol; for 24h;Reflux; Ethyl 4,4,4-trifluoro-3-oxobutanoate (5 mmol0.92 g), phenylhydrazine (5 mmol, 0.55 g) and 4-toluene sulfonic acid (TsOH,1 mmol, 0.17 g) were refluxed in 25 mL ethanol for 24 h. After cooling the reaction mixture, ethanol was evaporated and the residue was extracted with ethyl acetate (20 mL 3). The combined organic layer was then washed with sodium bicarbonate solution and dried with MgSO4. The crude product was purified through column chromatography. Compound 3 was obtained in 67% yield. Ketoenol tautomerism of compound 3 was existed as data showed from 1H, 13C NMR spectra. 1H NMR (500 MHz, acetone-d6) delta: 11.04(s, 1H, OH), 7.82 (d, J 8.0 Hz, 2H), 7.51 (t, J 7.5 Hz, 2H), 7.37 (t,J 7.5 Hz, 1H) ppm. 13C NMR (125 MHz, acetone-d6) delta: 206.6, 153.9,142.5 (q, 2JC-F 37.5 Hz) 139.1, 129.8, 128.0, 123.2122.3 (q,1JC-F 266.5 Hz, CF3), 86.7 ppm. 19F NMR (470 MHz, acetone-d6) delta: 63.66 (s, CF3) ppm.

  • 7
  • [ 207981-46-2 ]
  • [ 372-31-6 ]
  • [ 215124-11-1 ]
YieldReaction ConditionsOperation in experiment
39% In toluene; Step 1. Preparation of Ethyl 2,6-bis(trifluoromethyl)-4-oxo-4H-1-benzopyran-3-carboxylate To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22 mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodium hydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol) causing gas evolution. After gas evolution has subsided, <strong>[207981-46-2]2-fluoro-5-(trifluoromethyl)benzoyl chloride</strong> (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours, then heated to 105 C. for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether and the resulting solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a slightly sticky white solid. This solid was triturated with hexanes yielding the desired ester(3.05 g, 39%) as a white powder: mp 116-120.1 C. 1H NMR(CDCl3/300 MHz) 8.52 (d, 2H, J=1.6 Hz), 8.03 (dd, 1H, J=8.9, 2.2Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H, J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C14H8F6O4: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.
39% In toluene; EXAMPLE 82 STR104 Step 1. Preparation of Ethyl 2,6-bis(trifluoromethyl)-4-oxo-4H-1-benzopyran-3-carboxylate. To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22 mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodium hydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol) causing gas evolution. After gas evolution has subsided, <strong>[207981-46-2]2-fluoro-5-(trifluoromethyl)benzoyl chloride</strong> (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours, then heated to 105 C. for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether and the resulting solution was washed with H2 O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a slightly sticky white solid. This solid was triturated with hexanes yielding the desired ester(3.05 g, 39%) as a white powder: mp 116-120.1 C. 1 H NMR (CDCl3 /300 MHz) 8.52 (d, 2H, J=1.6 Hz), 8.03 (dd, 1H, J=8.9, 2.2Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H, J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C14 H8 F6 O4: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.
39% In toluene; Step 1. Preparation of Ethyl 2,6-bis(trifluoromethyl)-4-oxo-4H-1-benzopyran-3-carboxylate. To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22 mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodium hydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol) causing gas evolution. After gas evolution has subsided, <strong>[207981-46-2]2-fluoro-5-(trifluoromethyl)benzoyl chloride</strong> (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours, then heated to 105 C. for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether and the resulting solution was washed with H2 O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a slightly sticky white solid. This solid was triturated with hexanes yielding the desired ester(3.05 g, 39%) as a white powder: mp 116-120.1 C. 1 H NMR (CDCl3 /300 MHz) 8.52 (d, 2H, J=1.6 Hz), 8.03 (dd, 1H, J=8.9, 2.2 Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H, J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C14 H8 F6 O4: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.
  • 8
  • [ 372-31-6 ]
  • [ 96145-98-1 ]
YieldReaction ConditionsOperation in experiment
54.3 g (79%) With hydrogenchloride; phenylhydrazine; In methanol; (b) A mixture of 44 ml (0.3 mol) of ethyl trifluoroacetoacetate and 33 mL (335.4 mmol) of phenylhydrazine in 60 ml of methanol containing 6 ml of conc. HCl solution was refluxed with stirring for 1.5 hours. After adding activated charcoal with stirring, the hot mixture was filtered. The residue was washed with methanol (2*70 ml), diluted with water, and the resulting white solid was filtered. The solid was washed with hexane and dried to afford 54.3 g (79%) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole as a pale solid.
  • 9
  • [ 7504-94-1 ]
  • [ 372-31-6 ]
  • 1-(2-pyrimidinyl)-3-trifluoromethyl-5-hydroxypyrazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; acetic acid; (b) A mixture of 2 g (9 mmol) of 2-hydrazinopyrimidine and ethyl trifluoroacetoacetate (2.6 ml; 9.1 mmol) in 10 ml of acetic acid was refluxed for 60 hours with stirring under nitrogen and then cooled. The mixture was concentrated in vacuo, the residue was diluted with 100 ml of water, and the mixture was extracted with ethyl acetate (3*). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dried in vacuo to afford 700 mg of 1-(2-pyrimidinyl)-3-trifluoromethyl-5-hydroxypyrazole as a red gum.
  • 10
  • [ 1701-24-2 ]
  • [ 629-30-1 ]
  • [ 372-31-6 ]
  • [ 124467-00-1 ]
  • [ 1701-18-4 ]
YieldReaction ConditionsOperation in experiment
With aniline; In PPA; B2 (2E/Z, 4E) N-Isobutyl 3-methyl-11-(2-trifluoromethyl-4-quinolinyloxy)undeca-2,4-dienamide Starting from 2-trifluoromethyl-4-chloroquinoline and 1,7-heptanediol. Ethyl trifluoroacetoacetate (3.7 g) and aniline (1.8 ml) were reacted together in polyphosphoric acid according to Joullie et al, J. Med. Chem., 16, 134 (1973), to give 2-trifluoromethyl-4-hydroxyquinoline (1.8 g).
  • 11
  • [ 124-42-5 ]
  • [ 372-31-6 ]
  • [ 2836-44-4 ]
YieldReaction ConditionsOperation in experiment
85.7% As shown in Scheme 1, to a 250 mL round-bottomflask, trifluoroacetoacetate (0.05 mol), acetamidine hydrochloride (0.05 mol), sodium methoxide (0.075 mol),and ethanol (100 mL) were added and refluxed for 10 h. After that, the mixture was acidified with 1 mol/L HCl to pH 7. The crude products were extracted using ethylacetate to produce intermediate 1. Then, intermediate 1(0.05 mol), POCl3(0.1 mol), and CH3CN(120 mL) wereadded to a 250 mL round-bottom flask to react for 0.5 hat a reflux temperature, and then, diisopropylethylamine(0.06 mol) was added dropwise. After continuously refluxingfor 8 h, excess POCl3and CH3CNwere distilled, andthen, ice water mixture (60 mL) was added. Finally, themixture was alkalify with 5 mol/L to pH 9 and extractedusing CH2Cl2to give intermediate 2 (Xie et al. 2013).2-Methyl-6-(trifluoromethyl)pyrimidin-4-ol (1) White crystals;yield 85.7%; m.p. 140-142 C; 1H NMR (DMSO-d6,500 MHz, ppm) delta: 13.03 (s, 1H, pyrimidine-OH), 6.68 (s,1H, pyrimidine-H), 2.36 (s, 3H); 13C NMR (DMSO-d6,125 MHz, ppm) delta: 162.78, 162.16, 152.03 (q, J = 35.5 Hz),122.33, 120.15, 111.12, 21.74.
With sodium methylate; In ethanol; water; (1) To a suspension of ethyl trifluoroacetoacetate (18.4g, 0.1mol) and acetamidine hydrochloride (9.5g, 0.1mol) in ethanol (100ml) was dropwise added 28% sodium methylate (19.3g, 0.1mol) under cooling with ice. The resulting mixture was stirred at room temperature for 1 hour, and further refluxed for 12 hours. After cooling, the reaction mixture was evaporated, water (150ml) was added to the residue, then the mixture was neutralized with concentrated hydrochloric acid. The crystal separated was collected by filtration, washed with water, and dried to give 4-hydroxy-2-methyl-6-trifluoromethylpyrimidine (9.8g). m.p.:141-143 ?C 1H-NMR(CDCl3) delta 2.57(3H, s), 6.72(1H, s), 13.4(1H, br s). 1H-NMR(DMSO-d6) delta 2.36(3H, s), 6.67(1H, s). 19F-NMR(DMSO-d6) delta -72.13.
To 12.6 g of sodium methoxide (28% methanol solution), 3.1 g of acetoamidine hydrochloride and 3 g of 4,4,4- trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 800C for 20 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added, followed by extraction three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 2.4 g of 2-methyl-6-trifluoromethylpyrimidin-4-ol . 2-methyl-6-trifluoromethylpyrimidin-4-ol1H-NMR (DMSO-d6): 2.35(s,3H), 6.68(s,lH), 13.02(bs,lH)
  • 13
  • [ 57297-29-7 ]
  • [ 372-31-6 ]
  • [ 874880-33-8 ]
YieldReaction ConditionsOperation in experiment
52% With potassium carbonate; In water; at 20℃; for 0.25h;Microwave irradiation; General procedure: The corresponding amidine hydrochloride (2.54 mmol) and powdered K2CO3 (5.76 mmol) were dissolved in water (5.0 mL) in a 20-mL vessel. The beta-keto ester (2.31 mmol) was added and the resulting mixture was irradiated for 5?15 min (see Table 2). Upon the end of the reaction (TLC, hexanes/EtOAc, 5:1), the mixture was diluted with sat. aq NH4Cl (5.0 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried (anhyd Na2SO4) and filtered. The filtrate was rotary evaporated and the obtained crude product was purified by column chromatography [silica gel, hexane/EtOAc mixtures or recrystallized (EtOH)].
To 40 g of sodium methoxide (28percent methanol solution) , 5 g of <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong> and 7.63 g of 4, 4, 4-trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 800C for 10 hours and then heated under reflux for 12 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10percent hydrochloric acid was added and then a precipitated crystal was collected by filtration. This crystal was washed with water and then dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 4.6 g of 2-cyclopropyl-6- trifluoromethylpyrimidin-4-ol . 2-cyclopropyl-6-trifluoromethylpyrimidin-4-ol1H-NMR (DMSO-d6): 1.02-1.14 (m, 4H) , 1.96-2.03 (m, IH) , 6 . 58 ( s , IH ) , 13 . 21 (bs , lH )
  • 14
  • [ 109221-88-7 ]
  • [ 372-31-6 ]
  • [ 1257411-99-6 ]
  • 15
  • [ 62830-55-1 ]
  • [ 372-31-6 ]
  • [ 1257412-06-8 ]
  • 16
  • [ 123-72-8 ]
  • [ 372-31-6 ]
  • [ 27829-72-7 ]
  • 17
  • [ 59-88-1 ]
  • [ 372-31-6 ]
  • [ 96145-98-1 ]
YieldReaction ConditionsOperation in experiment
81% With potassium carbonate; In ethanol;Reflux; General procedure: A 3.9 g, 27 mmol of phenylhydrazine hydrochloride was added to 27 mmol of the corresponding ethyl 4-polyfluoroalkyl-3-oxo ester and 3.9 g, 30 mmol of K2CO3. The mixture was refluxed in 50 ml of ethanol for 3-4 h. The solvent was removed in vacuo. The precipitate was isolated and washed with water and hexane.
  • 18
  • [ 6100-60-3 ]
  • [ 372-31-6 ]
  • C11H7F3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With methanesulfonic acid; at 20℃; for 12h; General procedure: To a suspension of compound 1 (1 eq), compound 2 (1.2 eq), CH3SO3H was added in one portion. The mixture was stirred at RT 12 h. LC-MS showed that starting material was consumed completely. The reaction mixture was poured into ice-water (100 mL) and stirred for 30 min. The formed precipitate was filtered and washed with water and EA, dried to afford the crude compound 3 and use at the next step directly.
  • 19
  • [ 372-31-6 ]
  • [ 75-05-8 ]
  • [ 117724-63-7 ]
YieldReaction ConditionsOperation in experiment
85.05% Step 1: In a four-necked reaction flask equipped with a mechanical stirrer, thermometer and air duct, 92 gTrifluoroacetoacetate, 230 g of acetonitrile and 2.24 g of KOH, and the mixture was cooled in an ice bath to 0 to 25 C,Slowly enter the 39.4 g of chlorine and 21 g of hydrogen sulfide gas, ventilation time of about 3-5h. After the completion of access to the gas insulation reaction 1h, and then blow off the generated hydrogen chloride gas, excessive chlorine and hydrogen sulfide gas.Step 2: To the above reaction, dropwise add 112g of triethylamine. After adding dropwise, the mixture is heated to reflux and refluxed for 3 hours. The resulting triethylamine hydrochloride is filtered and the filtrate is distilled to recover the solvent.Step 3: temperature control 25-35 , dropping 30% sodium hydroxide solution 170g, insulation reaction 2 ~ 3h.Step four: 180g 30% hydrochloric acid solution for acidification, a large number of white precipitate precipitation. After the completion of the dropwise addition, the reaction was allowed to proceed for 1 h, followed by filtration and drying to obtain 92.55 g of the substance, content: 97.02%, yield: 85.05%.
  • 20
  • [ 62-55-5 ]
  • [ 372-31-6 ]
  • [ 117724-63-7 ]
YieldReaction ConditionsOperation in experiment
90.8% (1) into a chain130 kg of acetonitrile into the reactor,32 kg of thioacetamide was added with stirring,90 kg of ethyl trifluoroacetoacetate was added dropwise at 30 C,Drop finished,Continue to maintain the chain reaction for 2.5 hours. (2) to form a ringAfter the completion of the chain reaction,120 kg of tri-n-propylamine was added dropwise at 30 C,Dropping time for 1 hour,Drop finished,The temperature was raised to 70 C for 3 hours to form a ring-forming reaction. (3) hydrolysisAfter the ring-forming reaction,The acetonitrile, water and tri-n-propylamine were separated by vacuum distillation,Respectively, with water acetonitrile fraction and tri-n-propylamine fraction. After acetonitrile and tri-n-propylamine were removed,The reaction solution was cooled to 30 C,Add 45% NaOH alkaline solution 93kg,The temperature was raised to 55 C for 1 hour to carry out hydrolysis reaction.(4) acidificationAfter the hydrolysis reaction is complete,Cooling to 40 ,30% hydrochloric acid was added dropwise for acidification,Transferred to pH = 1-2, and then continue to cool to 0 ,Add 200kg of water,Stirring for 0.5 hours,Filter,Centrifugal,The filter cake is dried and dried2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid 82.0 kg,Content of 95.3%,Yield 90.8% (based on ethyl trifluoroacetoacetate).The raw materials used in the preparation are commercially available.
  • 21
  • [ 50-00-0 ]
  • [ 4089-07-0 ]
  • [ 372-31-6 ]
  • 5-ethoxycarbonyl-1,3-bis[2-ethoxy-1-(4-hydroxybenzyl)-2-oxoethyl]-3,4,5,6-tetrahydropyrimidin-1-iumtrifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% In aq. acetate buffer; at 20℃; for 24h;pH 5.9; General procedure: To a solution of the appropriate amino ester hydrochloride 2a?f (5.4 mmol) in acetate buffer (pH5.9) (1.5 mL) trifluoromethyl 1,3-dicarbonyl compound 1a?c (2.7 mmol) and formaldehyde 33percent aqueoussolution (11 or 40 mmol) were added. The resulting mixture was stirred for 24 h at room temperature, then itwas extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over Na2SO4 andevaporated in vacuo. The product was purified by column chromatography on Kieselgel 60 (chloroform?MeOH10:0?9:1 or hexane?EtOAc 10:0?7:3).
  • 23
  • [ 28710-97-6 ]
  • [ 372-31-6 ]
  • 6-hydroxy-2-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one [ No CAS ]
  • 24
  • ethanimidamide hydrochloride [ No CAS ]
  • [ 372-31-6 ]
  • [ 2836-44-4 ]
YieldReaction ConditionsOperation in experiment
90.1% In ethyl trifluoroacetate was added to the three vial (0.1mol),DBU (0.12 mol) was stirred in absolute ethanol (200 mL).Stir for 1 hour, add dropwise ethanol dissolution A solution of acetamidine hydrochloride (0.12 mol),After the addition,Heating back, TLC tracks the progress of the reaction,After the disappearance of the raw material point, the reaction is stopped and heated to reflux; the solvent is dried, the ice water is slightly cooled, and the pH is adjusted to 5-6 with dilute hydrochloric acid;Extract with ethyl acetate, separate the layers, and combine the organic phases.After solvent removal, a white solid was obtained.The mass was 16.03 g (theoretical value 17.81 g), and the yield was 90.1%.
 

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