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Chemical Structure| 34486-06-1 Chemical Structure| 34486-06-1

Structure of 34486-06-1

Chemical Structure| 34486-06-1

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Product Details of [ 34486-06-1 ]

CAS No. :34486-06-1
Formula : C6H4F3NO
M.W : 163.10
SMILES Code : OC1=NC(=CC=C1)C(F)(F)F
MDL No. :MFCD08061317
InChI Key :XXRUAAOADAPPII-UHFFFAOYSA-N
Pubchem ID :10154195

Safety of [ 34486-06-1 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301-H319
Precautionary Statements:P301+P310-P305+P351+P338
Class:6.1
UN#:2811
Packing Group:

Computational Chemistry of [ 34486-06-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 1
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 31.26
TPSA ?

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

33.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.45
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

1.75
Log Po/w (WLOGP)?

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

2.96
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.

1.33
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

1.89
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.88

Water Solubility

Log S (ESOL):?

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

-2.29
Solubility 0.834 mg/ml ; 0.00511 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.

-2.06
Solubility 1.41 mg/ml ; 0.00866 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

-2.33
Solubility 0.77 mg/ml ; 0.00472 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.

-6.05 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

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)

1.39

Application In Synthesis of [ 34486-06-1 ]

* 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 [ 34486-06-1 ]

[ 34486-06-1 ] Synthesis Path-Downstream   1~26

  • 1
  • [ 34486-06-1 ]
  • [ 15014-25-2 ]
  • 2-(3-Nitro-6-trifluoromethyl-pyridin-2-yl)-malonic acid dibenzyl ester [ No CAS ]
  • 2
  • [ 34486-06-1 ]
  • 5-nitro-6-(trifluoromethyl)pyridin-2-ol [ No CAS ]
  • [ 117519-07-0 ]
  • 3,5-dinitro-2-hydroxy-6-trifluoromethylpyridine [ No CAS ]
  • 3
  • [ 34486-06-1 ]
  • 6-chloro-3-nitro-2-(trifluoromethyl)pyridine [ No CAS ]
  • [ 117519-08-1 ]
  • 2-chloro-3,5-dinitro-6-trifluoromethylpyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
78.3% EXAMPLE 5 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting a 50:50 mixture of 2-fluoro-6-trifluoromethylpyridine and 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 100-105°C. Potassium hydroxide flake (95percent, 13.0 g, 2.22 mole equivalents), and water (113.9 g) were charged to a 250 ml round bottomed flask fitted with a condenser, agitator and contents thermometer. The contents were stirred to give a solution. 2-Fluoro-6-trifluoromethylpyridine (99.7percent, 8.27 g, 0.5 mole equivalents) and 2-chloro-6-trifluoromethylpyridine (99.0percent, 9.17 g, 0.5 mole equivalents) were added and the reaction mixture heated to 100° C. During the reaction the temperature rose to 105° C. The reaction mixture was sampled and analyzed and found to contain 0.9percent 2-fluoro-6-trifluoromethylpyridine and 98.4 percent 2-hydroxy-6-trifluoromethylpyridine. No 2-chloro-6-trifluoromethylpyridine was present. The reaction mixture was cooled to 5° C. Concentrated hydrochloric acid (36.0percent, 14.2 g) was added dropwise over 40 minutes and the temperature maintained below 5° C. The product slurry was stirred for a further 60 minutes at less than 5° C. The product was filtered and displacement washed with water (18.5 g). The title product was then dried under vacuum at 40° C.: isolated dry weight 12.9 g, strength 99.0percent; isolated yield 78.3percent.
EXAMPLE 7 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting a 50:50 mixture of 2-fluoro-6-trifluoromethylpyridine and 2-chloro-6-trifluoromethylpyridine with solid potassium hydroxide and t-amyl alcohol at 105-108° C. Potassium hydroxide flake (95percent, 13.0 g, 2.22 mole equivalents) and t-amyl alcohol (99percent, 73.9 g, 8.32 mole equivalents) were charged to a 250 ml round bottomed flask fitted with a condenser, agitator and contents thermometer. The contents were stirred to give a slurry. 2-Fluoro-6-trifluoromethylpyridine (99.7percent, 8.27 g, 0.5 mole equivalents) and 2-chloro-6-trifluoromethylpyridine (99.0percent, 9.17 g, 0.5 mole equivalents) were added and the reaction mixture heated to 105° C. (slight reflux). During the reaction the temperature rose to 108° C. The reaction mixture was sampled after 4 hours and found to contain 0.2percent 2-fluoro-6-trifluoromethylpyridine and 93.6percent 2-hydroxy-6-trifluoromethylpyridine. No 2-chloro-6-trifluoromethylpyridine was present. The reaction mixture was cooled to 80° C. t-Amyl alcohol was distilled off to 108° C. and the reaction mixture was cooled to 40° C. Water (4.6 g) was added. Water and t-amyl alcohol were distilled off to a temperature of 110° C. The reaction mixture was cooled to 50° C. and water (79.6 g) was added. The reaction was cooled to 5° C. and concentrated hydrochloric acid (36.0percent, 14.2 g) added dropwise over 40 minutes while the temperature was maintained below 5° C. The product slurry was stirred for a further 60 minutes at less than 5° C. The product was filtered off and displacement washed with water (18.5 g). The title product was then dried under vacuum at 40° C.: isolated dry,weight 8.2 g, strength 97.5percent; isolated yield 49.0percent (residual t-amyl alcohol left after distillation led to yield losses).
  • 5
  • [ 34486-06-1 ]
  • 5-Trifluoromethyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one [ No CAS ]
  • 6
  • [ 95360-33-1 ]
  • [ 34486-06-1 ]
  • [ 187327-30-6 ]
YieldReaction ConditionsOperation in experiment
83% With sodium hydroxide; sodium iodide; In hexane; N,N-dimethyl-formamide; toluene; EXAMPLE 2 This Example illustrates the preparation of methyl 2-(6-trifluoromethylpyrid-2-yloxymethyl)phenylacetate (Compound No.3 in Table 1) and its conversion to the corresponding 3-methoxyacrylate (Compound No.177 in Table I of EP-A-0278595). A mixture of <strong>[34486-06-1]2-hydroxy-6-trifluoromethylpyridine</strong> (2.0 g, 12.3 mmol), sodium hydroxide (0.52 g, 12.9 mmol) and 15-crown-5 (1 drop) in dry toluene (25 ml) were stirred at reflux for 2 hours. The toluene was removed under reduced pressure and the white salt residue was dissolved in dry DMF (15 ml). Methyl 2-chloromethylphenylacetate (2.44 g, 12.3 mmol) in dry DMF (15 ml) was added dropwise along with sodium iodide (10 mg). The mixture was stirred at 75° C. for 2 hours, poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the ether removed in vacuo leaving an oil which was purified by column chromatography (silica eluted with 10percent ethyl acetate in hexane) to give methyl 2-(6-tri-fluoromethylpyrid-2-yloxymethyl)phenylacetate (3.3 g, 83percent) (Compound No.5 in Table 1) as a yellow oil; 1 H NMR (270 MHz)delta: 3.68(3H,s), 3.84(2H,s), 5.46(2H,s), 6.89(1H,d), 7,20-7.70(6H,m) ppm.
83% A mixture of <strong>[34486-06-1]2-hydroxy-6-trifluoromethylpyridine</strong> (2.0 g, 12.3 mmol), sodium hydroxide (0.52 g, 12.9 mmol) and 15-crown-S (1 drop) in dry toluene (25 mL) was stirred under reflux for 2 hours. Toluene was removed under reduced pressure and the white salt residue was dissolved in dry dimethylformamide (DMF) (15 mL). Methyl 2-chloromethylphenylacetate (2.44 g, 12.3 mmol) in dry DMF (15 mL) was added dropwise along with sodium iodide (10 mg). The mixture was stirred at 75 °C for 2 hours, then poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the remaining ether removed in vacuo leaving an oil, which was purified by column chromatography (silica eluted with 10percent ethyl acetate in hexane) to give methyl 2-(6-tri-fluoromethylpyrid-2-yloxymethyl)phenylacetate(3.3 g, 83percent).
  • 7
  • aqueous potassium hydroxide [ No CAS ]
  • [ 7664-93-9 ]
  • [ 39890-95-4 ]
  • [ 34486-06-1 ]
YieldReaction ConditionsOperation in experiment
92% With potassium hydroxide; sodium chloride; EXAMPLE 1 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 150° C. under autogenous pressure. 2-Chloro-6-trifluoromethylpyridine (10.0 g; 55.1 mmol; 1 equiv) was charged to a 100 ml Hastelloy C Parr reactor, the reactor sealed and pressure tested with nitrogen. When a sealed system had been achieved, the pressure was released, the reactor resealed, and heated to 150° C. Potassium hydroxide solution (10percent strength; 68.0 g; 121.1 mmol; 2.2 equiv) was added via an HPLC pump over 1 hour, while the mixture was maintained at 150° C. Addition of base caused the pressure to rise to 5 bar. The reaction mixture was held at this temperature and pressure for a further 5 hours. Following this period the reactor was cooled, dismantled and sodium chloride (5 g) added. The solution was cooled to 5° C., acidified to pH 5-6 by the addition of concentrated sulphuric acid, filtered and pulled dry. The filter cake was washed with water (10 g), pulled dry, discharged and allowed to dry overnight to afford 2-hydroxy-6-trifluoromethylpyridine as a colourless powder (9.5 g; 95percent strength; 92percent isolated yield).
  • 8
  • [ 39890-95-4 ]
  • [ 34486-06-1 ]
YieldReaction ConditionsOperation in experiment
80.8% With potassium hydroxide; In tert-butyl alcohol; at 70℃; for 8h; (3), 1500 g of t-butanol, 140 g of potassium hydroxide and 2-chloro-6-trifluoromethylpyridine prepared in step (2) were added to a 3 L reaction flask, and the temperature was raised to 70 ° C,Insulation reaction 8 hours,After completion of the reaction, tert-butanol was removed under reduced pressure, 550 g of ethyl acetate and 550 g of water were added and stirred,The organic layer was washed with 370 g of saturated brine, dried over 100 g of anhydrous sodium sulfate, and the ethyl acetate was removed by steaming To give crude 172.4 g;(4), the crude product prepared in step (3) was added to 150 g of ethyl acetate, heated to 70 ° C, stirred and dissolved, and 1200 g of petroleum ether was added dropwise,After the addition of petroleum ether, the mixture was cooled to 2 ° C, solid crystals were precipitated, and the solid was filtered. The solid was washed with 50 g of petroleum ether and dried at 70 ° C,To obtain 131.2 g of 2-hydroxy-6-trifluoromethylpyridine as a pale yellow solid powder in a yield of 80.8percent.
73% With sodium hydroxide; EXAMPLE 2 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-chloro-6-trifluoromethylpyridine with aqueous sodium hydroxide at 150° C. under autogenous pressure. 2-Chloro-6-trifluoromethylpyridine (8.05 g at 98percent strength; 43.2 mmol; 1 equiv) was charged to a Parr reactor, pressure tested at 100 psi. The pressure was released and the reactor heated to 150° C. Sodium hydroxide solution (9.823percent strength; 40.1 g; 98.5 mmol; 2.28 equiv) was added via an HPLC pump over 2 hours 20 minutes and the reaction mixture maintained at 150° C. for a further 4 hours. The mixture was cooled, unreacted 2-chloro-6-trifluoromethylpyridine extracted with methylene chloride, and the aqueous phase acidified with hydrochloric acid and filtered to afford 2-hydroxy-6-trifluoromethylpyridine (5.615 g; 93percent strength; 73percent isolated yield). Further product was obtained by extraction of the filtrates with methylene chloride.
2-chloro-6-trifluoromethylpyridine(? 99percent) 750 kg (4.01 Kmol) and1100kg-2000kg water is added to the reactorThen add 950 kg (9.15 Kmol) of potassium hydroxide (95percent).Potassium hydroxide can also be first formulated into an aqueous solution and put into the reactor.Raise the temperature to 120-170°C and stir the reaction at a pressure of about 0.3-0.8 MPa for 8 hours.After the sample is qualified (the content of 2-chloro-6-trifluoromethylpyridine is less than 0.1percent), it is transferred to the neutralizer.Transfer to the former neutralization kettle and add a certain amount of water first, and add 1500-3000kg of water to the medium capacity kettle.The amount of water added in the neutralization tank can be adjusted appropriately after the neutralization and the pulp concentration. The amount of water is too less than the pulp concentration is not conducive to stirring and discharging.The volume of water that has passed through the Ambassador has increased. After the material is transferred, it is neutralized with hydrochloric acid and the pH is 5-6.Neutralization process temperature control is less than 30 °C,After neutralization and cooling to 5-10°C,After centrifuging, the material enters the washing kettle.After adding 2000kg of water and water, it is centrifuged twice.The material is dried after the second centrifugation.Dry to give 2-hydroxy-6-trifluoromethylpyridine.
  • 9
  • aqueous potassium hydroxide [ No CAS ]
  • 2-fluoro-6-(trifluoromethyl)pyridine [ No CAS ]
  • [ 34486-06-1 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide; In water; EXAMPLE 1 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-fluoro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 100° C. Potassium hydroxide (95percent, 20.5 g, 2.22 mole equivalents) and water (180 ml) were charged to a 500 ml round bottomed flask equipped with mechanical stirrer, reflux condenser and contents thermometer. 2-Fluoro-6-trifluoromethylpyridine (26.0 g, 99.5percent strength) was charged to the aqueous base. The resulting two-phase solution was heated to 100° C. The reaction mixture was sampled after 2 hours at 100° C. and qualitative GC analysis showed 19.29 area percent 2-hydroxy-6-trifluoromethylpyridine and 78.9 area percent 2-fluoro-6-trifluoromethylpyridine. The reaction mixture was left to stir for an additional 3 hours at 100° C. before being resampled. Qualitative GC analysis showed 99.51 area percent 2-hydroxy-6-trifluoromethylpyridine and 0.12 area percent 2-fluoro-6-trifluoromethylpyridine. The reaction mixture was cooled to below 10° C. and acidified to pH 5 (using pH paper) with concentrated hydrochloric acid (36percent, 21.7 g, 1.36 mole equivalents) while maintaining the temperature below 10° C. A white product was isolated by filtration and the filtrates used to wash out the flask. The filter cake was sucked dry, washed with cold water (29.1 g) and sucked dry again. The product was dried in an evacuated oven at 40° C. overnight: isolated dry weight 23.93 g at 97.74percent; yield, 91.4percent; NMR 1 H and 13 C conforms to structure; mp (Gallenkamp melting point apparatus) 126.7-127.6° C.
With potassium hydroxide; In water; EXAMPLE 2 This Example further illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-fluoro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 100° C. Potassium hydroxide (95percent, 20.5 g, 2.22 mole equivalents) and water (80 ml) were charged to a 250 ml round bottomed flask equipped with mechanical stirrer, reflux condenser and contents thermometer. 2-Fluoro-6-trifluoromethylpyridine (26.0 g, 99.5percent strength) was charged to the aqueous base. The resulting two-phase solution was heated to 100° C. The reaction mixture was sampled after 2 hours at 100° C. and qualitative GC analysis showed 90.96 area percent 2-hydroxy-6-trifluoromethylpyridine and 9.03 area percent 2-fluoro-6-trifluoromethylpyridine. The reaction mixture was left to stir for an additional 2 hours at 100° C. before being resampled. Qualitative GC analysis showed 98.59 area percent 2-hydroxy-6-trifluoromethylpyridine and 1.39 area percent 2-fluoro-6-trifluoromethylpyridine. After stirring another hour, the reaction mixture was cooled to below 10° C. and acidified to pH 5 (using pH paper) with concentrated hydrochloric acid (36percent, 21.2 g, 1.33 mole equivalents) while maintaining the temperature below 10° C. A white product was isolated by filtration and the filtrates used to wash out the flask. The filter cake was sucked dry, washed with cold water (20 g) and sucked dry again. The product was dried in an evacuated oven at 40°C. overnight: isolated dry weight 25.43 g at 87.79percent; yield 87.2percent.
With potassium hydroxide; In water; EXAMPLE 3 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-fluoro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 80° C. Potassium hydroxide (95percent, 2.6 g, 2.20 mole equivalents) and water (22.5 g) were charged to a 100 ml round bottomed flask equipped with mechanical stirrer, reflux condenser and contents thermometer. 2-Fluoro-6-trifluoromethylpyridine (3.3 g, 99.5percent strength) was charged to the aqueous base. The resulting two-phase solution was heated to 80° C. The reaction mixture was sampled after 13 hours at 80° C. and qualitative GC analysis showed 47.3 area percent 2-hydroboxy-6-trifluoromethylpyridine and 46.2 area percent starting material.
With potassium hydroxide; In water; EXAMPLE 9 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-fluoro-6-trifluoromethylpyridine with aqueous potassium hydroxide (35percent) at 100° C. Potassium hydroxide (95percent, 33.8 g, 2.2 mole equivalents) and water (63.2 g) were charged to a 250 ml round bottomed flask equipped with mechanical stirrer, reflux condenser and contents thermometer. The contents were stirred to give a solution, and heated to 100° C. 2-Fluoro-6-trifluoromethylpyridine (42.5 g. 99.2percent strength) was added dropwise over 133 minutes maintaining the reaction temperature at 100° C. The reaction mixture was sampled at the end of the addition, and qualitative GC analysis showed 92.8 area percent 2-hydroxy-6-trifluoromethylpyridine and 6.5 area percent starting material.

  • 10
  • 2-fluoro-6-(trifluoromethyl)pyridine [ No CAS ]
  • [ 39890-95-4 ]
  • [ 34486-06-1 ]
YieldReaction ConditionsOperation in experiment
97% With hydrogenchloride; In water; EXAMPLE 8 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting a 95:5 mixture of 2-fluoro-6-trifluoromethylpyridine and 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 115-130° C. Potassium hydroxide flake (95percent, 25.9 g, 2.22 mole equivalents) and water (24.6 g, 6.84 mole equivalents) were charged to a 250 ml round bottomed flask fitted with a condenser, agitator and (contents thermometer. The contents were stirred to give a solution and heated to 130° C. (reflux). A mixture of 2-fluoro-6-trifluoromethylpyridine (99.2percent, 31.6 g, 0.95 mole equivalents) and 2-chloro-6-trifluoromethylpyridine (100percent, 1.8 g, 0.05 mole equivalents) was add d dropwise over 1 hour maintaining a gentle reflux (115-120° C.). When the addition was complete the reaction mixture was held for 4 hours at 115° C. (reflux). The reaction mixture was cooled to 50° C. and water (79 g) added. Hydrochloric acid (approximately 27.4 g, 36percent strength) was then added dropwise over 30 minutes maintaining a temperature of 50° C. to give a pH of 5. The resulting slurry was stirred for a further 10 minutes at 50° C. and then cooled to 0-5° C. and the pH readjusted to 5. The slurry was held for a further 30 minutes at 0-5° C. The product was filtered and displacement washed with water (37 g). The title product was then dried under vacuum at 40° C.: isolated dry weight 31.7 g, yield 97percent (assuming a product strength of 100percent).
In water; EXAMPLE 6 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reading a 50:50 mixture of 2-fluoro-6-trifluoromethylpyridine and 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 150° C. Potassium hydroxide flake (95percent, 82.1 g, 13.9 mole equivalents) and water (19.5 g) were charged to a 250 ml round bottom flask fitted with a condenser, agitator and contents thermometer. The contents were stirred to give a solution. 2-Fluoro-6-trifluoromethyl-pyridine (99.7percent, 8.27 g, 0.5 mole equivalents) and 2-chloro-6-trifluoromethylpyridine (99.0percent, 9.17 g, 0.5 mole equivalents) were added and the reaction mixture heated to 150° C. and held for 2 hours. The reaction mixture was sampled and analyzed and found to contain 0.6percent, 2-fluoro-6-trifluoromethylpyridine and 99.4percent 2-hydroxy-6-trifluoromethylpyridine.
  • 11
  • 2-fluoro-6-(trifluoromethyl)pyridine [ No CAS ]
  • [ 34486-06-1 ]
YieldReaction ConditionsOperation in experiment
66% With water; potassium hydroxide; at 100℃; The reaction mixture of 2-fluoro-6- (trifluoromethyl) pyridine (660 mg, 4 mmol) and KOH (493 mmol, 8.8 mmol) in water (5 mL) was stirred at 100 for overnight. After completed, the mixture was neutralized with 1N hydrochloride to pH7. Then the precipitate was filtered and dried to give the product as white solid (430 mg in 66percentyield) . MS (M+H) + 164.0.
With sodium hydroxide; In water; EXAMPLE 4 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-fluoro-6-trifluoromethylpyridine with aqueous sodium hydroxide at 100° C. Sodium hydroxide (98percent, 1.8 g, 2.20 mole equivalents) and water (16.2 g) were charged to a 100 ml round bottomed flask equipped with mechanical stirrer, reflux condenser and contents thermometer. 2-Fluoro-6-trifluoromethylpyridine (3.3 g 99.5percent strength) was charged to the aqueous base. The resulting two-phase solution was heated to 100° C. The reaction mixture was sampled after 12 hours at 100° C. and 48 hours stirring at ambient temperature. Analysis by qualitative GC showed 99.65 area percent 2-hydroxy-6-trifluoropyridine and no starting material.
  • 12
  • [ 34486-06-1 ]
  • [ 630-17-1 ]
  • [ 1403386-98-0 ]
  • 13
  • [ 34486-06-1 ]
  • [ 630-17-1 ]
  • [ 1403386-99-1 ]
YieldReaction ConditionsOperation in experiment
15% Step 1 : 2-(Neopentyloxy)-6-(trifluoromethyl)pyridine (P12a)To a solution of <strong>[34486-06-1]6-(trifluoromethyl)pyridin-2-ol</strong> (5.00 g, 30.7 mmol) in dry DMF (50 mL) was added NaH (3.71 g, 92.1 mmol) under N2 and the mixture was stirred at rt for 1 h. Then 1- bromo-2,2-dimethylpropane (11.6 g, 76.7 mmol) was added and the resulting mixture was heated at 100°C overnight, cooled, quenched with water (10 mL) and extracted with EA twice. The combined organic layers were washed with brine (3 x), concentrated and purified by CC on NH silica gel (PE/EA = 100/1) to give compound P12a (1.05 g, 15percent) as an oil.
  • 14
  • [ 34486-06-1 ]
  • [ 74-88-4 ]
  • [ 34486-18-5 ]
YieldReaction ConditionsOperation in experiment
59.8% With silver (II) carbonate; In dichloromethane; for 24h;Darkness; 2-methoxy-6-ftrifluoromethyl)pyridine To a solution of <strong>[34486-06-1]6-(trifluoromethyl)pyridin-2-ol</strong> (10.0 g, 10.0 g, 61.3 mmol) in dichloromethane (3 ml/mmol, 184 ml) was added silver carbonate (22.8 g, 82.8 mmol, 3.75 mL) and iodomethane (87.0 g, 613 mmol, 38.2 mL) and stirred in the dark for 24 hours. The reaction mixture was then filtered through Celite and washed with dichloromethane. The filtrate was concentrated at 30 oC at 250 mbar, silica added and the residue was purified by chromatography eluting with 0-10percent ethyl acetate/hexane. Fractions containing product were combined to give 2-methoxy-6-(trifluoromethyl)pyridine (6.49 g, 36.6 mmol, 59.8percent yield). IHNMR (CDC13): delta 7.69 ft, J =8.1 Hz, IH) 7.25 (d, J=7.5 Hz, 1 H) 6.91 (d, J=8.6 Hz, 1 H) 3.98 (s, 3 H);
59.8% With silver carbonate; In dichloromethane; 2-methoxy-6-(trifluoromethyl)pyridine To a solution of <strong>[34486-06-1]6-(trifluoromethyl)pyridin-2-ol</strong> (10.0 g, 10.0 g, 61.3 mmol) in dichloromethane (3 ml/mmol, 184 ml) was added silver carbonate (22.8 g, 82.8 mmol, 3.75 mL) and iodomethane (87.0 g, 613 mmol, 38.2 mL) and stirred in the dark for 24 hours. The reaction mixture was then filtered through Celite and washed with dichloromethane. The filtrate was concentrated at 30° C. at 250 mbar, silica added and the residue was purified by chromatography eluting with 0-10percent ethyl acetate/hexane. Fractions containing product were combined to give 2-methoxy-6-(trifluoromethyl)pyridine (6.49 g, 36.6 mmol, 59.8percent yield). 1H NMR (CDCl3): delta 7.69 (t, J=8.1 Hz, 1H) 7.25 (d, J=7.5 Hz, 1H) 6.91 (d, J=8.6 Hz, 1H) 3.98 (s, 3H);
17% With silver carbonate; In dichloromethane; at 20℃; for 24h;Darkness; The suspension of 6- (trifluoromethyl) pyridin-2-ol (430 mg, 2.64 mmol) , iodomethane (3.75 g, 26.4mmol) and Ag 2CO 3 (982 mg, 3.56 mmol) in CH 2Cl 2 (8 mL) was stirred at room temperature in dark for 24 hrs. After completed, the mixture was filtered and the solvent was evaporated in vacuo at 30 . The residue was purified by column chromatography (PE/EA = 5/1) to give the product (80 mg in 17percentyield) . 1H NMR (400 MHz, CDCl 3) delta 7.76 ?7.59 (m, 1H) , 7.24 (d, J = 7.3 Hz, 1H) , 6.91 (d, J = 8.4 Hz, 1H) , 3.98 (s, 3H) .
  • 16
  • [ 34486-06-1 ]
  • [ 1429874-13-4 ]
  • 17
  • [ 34486-06-1 ]
  • [ 1429874-14-5 ]
  • 18
  • [ 34486-06-1 ]
  • [ 1429874-15-6 ]
  • 19
  • [ 34486-06-1 ]
  • [ 1429873-64-2 ]
  • 20
  • [ 117428-51-0 ]
  • [ 34486-06-1 ]
  • picoxystrobin [ No CAS ]
  • 21
  • [ 34486-06-1 ]
  • [ 1240518-41-5 ]
  • 4-(6-(trifluoromethyl)pyridin-2-yloxy)-2-fluoro-6-methoxybenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 0.166667h;Microwave irradiation; A mixture of 2,4-difluoro-6-methoxybenzonitrile(0.200g, 1.183mmol), 2-hydroxy-6- trifluoromethylpyridine(0.231g, 1.419mmol), potassium carbonate(0.196g, 1.419mmol), and NMP(2mL), were heated via microwave for 10minutes at 130C. LCMS shows the desired product. The crude reaction was used in the next step without purification.
  • 22
  • [ 34486-06-1 ]
  • 1-(5-chloro-4-fluoro-2-hydroxy-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)phenyl)ethan-1-one [ No CAS ]
  • 23
  • [ 34486-06-1 ]
  • [ 117428-49-6 ]
  • [ 117428-22-5 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 24h; The methoxy acrylate compound 3o (1.0 mmol),<strong>[34486-06-1]6-trifluoromethyl-2-hydroxypyridine</strong> (1.3 mmol)And potassium carbonate (2.0 mmol) was added to 5.0 mL of DMF.After reacting for 24 hours in an oil bath at 50 C, the reaction was stopped and cooled to room temperature.20 mL of water and 20 mL of ethyl acetate were added to the reaction solution for extraction.The aqueous phase was washed 3 times with 20 mL of ethyl acetate.After combining the organic phases, wash with 20 mL of saturated sodium chloride.The organic phase was dried over anhydrous sodium sulfate. After filtering and evaporating the solvent under reduced pressure,The residue was separated and purified by column chromatography on silica gel.The volume ratio of the eluent used is ethyl acetate: petroleum ether = 1:20 ~ 1:10,The pure picoxystrobin 6 was obtained in a yield of 98%
  • 24
  • [ 34486-06-1 ]
  • [ 110661-91-1 ]
  • tert-butyl 4-((6-(trifluoromethyl)pyridin-2-yl)oxy)butanoate [ No CAS ]
  • 25
  • [ 34486-06-1 ]
  • 4-((6-(trifluoromethyl)pyridin-2-yl)oxy)butanoic acid hydrochloride [ No CAS ]
  • 26
  • [ 34486-06-1 ]
  • N-(5-methylthiazol-2-yl)-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)butanamide [ No CAS ]
 

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