Structure of 98-17-9
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Canale, Vittorio ; Czekajewska, Joanna ; Klesiewicz, Karolina ; Papiez, Monika ; Kuziak, Agata ; Witek, Karolina , et al.
Abstract: The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our inhouse libraries were screened against a wide panel of clin. relevant Gram-pos. and Gram-neg. bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-pos. bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 μg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-neg. bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-pos. bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents.
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Keywords: Arylurea derivatives ; Antibacterial properties ; Anti-MRSA activity ; Anti-VRE activity ; Anti-LRSE activity ; Depolarization of bacterial cell membrane
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Purchased from AmBeed: 122536-76-9 ; 936-59-4 ; 135632-53-0 ; 404-71-7 ; 73874-95-0 ; 372-20-3 ; 98-17-9 ; 402-45-9 ; 57260-71-6 ; 122536-77-0 ; 444-30-4 ; 165800-03-3 ; 150-19-6 ; 1195-45-5 ; 2909-38-8 ; 165800-03-3
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CAS No. : | 98-17-9 |
Formula : | C7H5F3O |
M.W : | 162.11 |
SMILES Code : | OC1=CC=CC(C(F)(F)F)=C1 |
MDL No. : | MFCD00002299 |
InChI Key : | UGEJOEBBMPOJMT-UHFFFAOYSA-N |
Pubchem ID : | 7376 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H227-H315-H319-H335-H402 |
Precautionary Statements: | P210-P261-P264-P271-P273-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 33.47 |
TPSA ? Topological Polar Surface Area: Calculated from |
20.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.51 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.95 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.56 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.35 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.59 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.04 |
Solubility | 0.147 mg/ml ; 0.000909 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.04 |
Solubility | 0.149 mg/ml ; 0.000918 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.7 |
Solubility | 0.325 mg/ml ; 0.002 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.19 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 140℃; for 6 h; | To 500mL three-necked flask equipped with a thermometer, was added DMF (200ml), between sequentially added trifluoromethylphenol (0.26mol, 42.2g), potassium carbonate (0.266mol, 37.2g), 2-chloro-6-carboxy pyridine (0.2mol, 31.6g), cuprous chloride (1.0 g of), heated to 140 deg.] C, the reaction 6.0H, cooled to room temperature, the reaction solution was poured into 600ml of ice water, pH = 3 adjusted with concentrated brine, and the precipitated solid was pumped was filtered off, washed with water, dried to obtain a white solid, yield: 75percent |
75% | With potassium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 140℃; for 8 h; | DMF (200 ml) was added to a 500 mL three-necked flask equipped with a thermometer, followed by the addition of m-trifluoromethylphenol.(0.26 mol, 42.2 g), potassium carbonate (0.266 mol, 37.2 g), 2-chloro-6-carboxypyridine (0.2 mol, 31.6 g) andCuprous chloride (1.0 g), warmed to 140 ° C, reacted for 8.0 h, cooled to room temperature, and poured into 600 ml of ice water.The pH of the brine was adjusted to 3, and the solid was precipitated, suction filtered, washed with water, and dried to give a white solid. Yield: 75percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.1% | With nitric acid; acetic acid; at 20 - 40℃; for 1h; | General procedure: An appropriate phenol (3) (150 mmol) was dissolved in glacial acetic acid (50 mL), and the solution was stirred and maintained at 40 C. Then, a solution containing 11 mL of 65% HNO3 and 30 mL of glacial acetic acid was added drop wise over 15 min. The mixture was stirred at r.t. for 45 min and poured into ice-water (400 mL). The aqueous mixture was extracted four times with CHCl3 (100 mL). Next, the organic phases were collected, dried with Na2SO4, evaporated and purified by column chromatography (4a, 4c, 4e) or crystallisation from ethanol (4b). Compound 4d was used for the next step without further purification [17]. |
16% | With nitric acid; acetic acid; In water; at 0 - 20℃; for 17.5h; | To a solution of 3-(trifluoromethyl)phenol (5.0 g, 30.86 mmol) in acetic acid (50 mL) was added 60% aqueous nitric acid (3.5 mL) dropwise at 0 C. Then the mixture was stirred at this temperature for 1.5 h and stirring was continued at RT for 16 h. The mixture was poured into ice water (80 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by combiflash column chromatography using 5% ethyl acetate in hexane as eluent to afford the titled compound (1.0 g, 16%); 1H NMR (400 MHz, DMSO-d6): δ 11.75 (bs, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.41 (d, J=1.4 Hz, 1H), 7.32 (dd, J=1.4 Hz, J=8.3 Hz, 1H); LC-MS: m/z 206.0 (M-1)-. |
With nitric acid; In water; at 0℃; for 1h; | The subtitle compound was prepared by using 3-(l,l,l-trifluoromethyl)phenol (5.0g)which was cooled to 0 C and 65% nitric acid (6ml) was added dropwise. After the addition,the mixture was kept at 0 C for 1 hour. This was diluted with saturated sodium acetatesolution, extracted with ethyl acetate, dried and concentrated under reduced pressure to givean oil. Yield 3.67gMS: ESI (+ve) 206 (M+l) |
With nitric acid; In water; at 20℃; for 1h; | Reference Production Example 9 To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol. [Show Image] 1H-NMR (CDCl3) δ: 10.59 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.48-7.46 (m, 1H), 7.27-7.23 (m, 1H) | |
With nitric acid; at 20℃; for 1h; | Reference Production Example 9To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.1H-NMR (CDCl3) δ: 10.59 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.48-7.46 (m, 1H), 7.27-7.23 (m, 1H)2-amino-5-trifluoromethylphenol was obtained according to the same manner as that of Reference Production Example 1, using 2-nitro-5-trifluoromethylphenol instead of 4-propyl-2-nitrophenol.1H-NMR (CDCl3+DMSO-d6) δ: 9.03 (br s, 1H), 7.01 (d, J=1.8 Hz, 1H), 6.95-6.91 (m, 1H), 6.71-6.66 (m, 1H), 4.13 (br s, 2H)A mixture of 1.30 g of 2-amino-5-trifluoromethylphenol, 0.9 g of isonicotinic acid, 1.83 g of WSC and 15 ml of pyridine was stirred while heating at 80 C. for three hours. The mixture was cooled to room temperature, and then water was poured. Precipitated solid was filtered and washed with water, and then dried under reduced pressure to give 1.5 g of N-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide.1H-NMR (DMSO-d6) δ: 8.82-8.76 (m, 2H), 7.98-7.93 (m, 1H), 7.89-7.85 (m, 2H), 7.23-7.17 (m, 2H) | |
Reference Production Example 9To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.1H-NMR (CDC13) δ: 10.59 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.48-7.46 (m, 1H), 7.27-7.23 (m, 1H) | ||
With nitric acid; at 20℃; for 1h; | To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.-NMR (CDC13) δ: 10.59 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.48-7.46 (m, 1H), 7.27-7.23 (m,1H) | |
To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.1 H-NMR (CDC13) δ: 10.59 (s, IH), 8.25 (d, J=8.8 Hz, IH), 7.48-7.46 (m, IH), 7.27-7.23 (m,IH) | ||
With nitric acid; In water; acetic acid; at 20℃; for 4h; | Reference Production Example 9To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.1H-NMR (CDC13) δ: 10.59 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.48-7.46 (m, 1H), 7.27-7.23 (m,1H) | |
With nitric acid; at 20℃; for 1h; | Reference Production Example 9To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.1 H-NMR (CDC13) δ: 10.59 (s, IH), 8.25 (d, J=8.8 Hz, IH), 7.48-7.46 (m, IH), 7.27-7.23 (m,IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In hexane; N,N-dimethyl-formamide; mineral oil; | (1) Production of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine as an intermediate product 3.34 g (0.187*1.1 mol) of 3-(trifluoromethyl) phenol was dissolved in about 30 ml of dimethyl formamide. The solution was further mixed with 0.78 g (ca. 60% in mineral oil; 0.0187*1.04 mol) of sodium hydride and then with 5.00 g (0.0187 mol) of <strong>[117873-72-0]2,6-dibromo-4-methoxy pyridine</strong>. After stirring at about 120 C. for about 2 hours, the mixture was allowed to stand for cooling to room temperature. After the reaction solution was distributed with hexane-saturated sodium bicarbonate water, the organic phase of the obtained solution was washed with saturated brine and dried with anhydrous sodium sulfate. The resultant solution was concentrated and then purified by silica gel column chromatography (eluding solution: ethyl acetate/hexane), and the obtained product was subjected to recrystallization using hexane, thereby obtaining an aimed product. Yield by weight: 3.23 g; yield by percentage: 50%; solid; melting point: 57 to 60 C.; 1 H-NMR (60 MHz, CDCl3, delta): 3.75 (3H, s), 6.26 (1H, d, J=2 Hz), 6.75 (1H, d, J=2 Hz), 7.0-7.6 (4H, complex). | |
In hexane-saturated sodium bicarbonate water; hexane; N,N-dimethyl-formamide; mineral oil; | (1) <Production of 2-bromo-4-methoxy-6-[3-(trifluoromethyl)phenoxy] pyridine as an intermediate product> 3-(trifluoromethyl) phenol (3.34 g; 0.0187*1.1 mol) was dissolved in dimethyl formamide (about 30 ml). Further, sodium hydride [0.78 g (ca. 60% in mineral oil), 0.0187*1.0 mol] and then <strong>[117873-72-0]2,6-dibromo-4-methoxy pyridine</strong> (5.00 g, 0.0187 mol) were added to the solution. The obtained solution was stirred at about 120 C. for about 2 hours and, thereafter, allowed so as to stand and cooled to room temperature. The obtained reaction solution was distributed in hexane-saturated sodium bicarbonate water. The organic phase separated from the reaction solution was washed with saturated brine, and dried with anhydrous sodium sulfate. The resultant solution was concentrated and then purified by silica gel column chromatography (eluding solution: ethyl acetate/hexane), and the obtained purified product was subjected to recrystallization using hexane, thereby obtaining an aimed product. Yield weight: 3.23 g; yield percentage: 50%; solid; melting point: 57 to 60 C.; 1 H-NMR (60 MHz, CDCl3, delta): 3.75(3H, s), 6.26(1H, d, J=2 Hz), 6.75(1H, d, J=2 Hz), 7.0-7.6(4H, complex). | |
In hexane-saturated sodium bicarbonate water; hexane; N,N-dimethyl-formamide; mineral oil; | (1) Production of 2-bromo-4-methoxy-6-[3-(trifluoromethyl)phenoxy] pyridine as an intermediate 3-(trifluoromethyl) phenol (3.34 g; 0.0187*1.1 mol) was dissolved in dimethyl formamide (hereinafter referred to merely as "DMF") (approximately 30 ml). Further, sodium hydride [0.78 g (ca. 60% in mineral oil), 0.0187*1.0 mol] and then <strong>[117873-72-0]2,6-dibromo-4-methoxy pyridine</strong> (5.00 g, 0.0187 mol) were added to the solution. The obtained solution was stirred at about 120 C. for about 2 hours and, thereafter, allowed to stand so as to be cooled to room temperature. The obtained reaction solution was distributed in hexane-saturated sodium bicarbonate water. The organic phase separated from the reaction solution was washed with saturated brine, and dried with anhydrous sodium sulfate. The resultant solution was concentrated and then purified by silica gel column chromatography (eluding solution: ethyl acetate/hexane), and the obtained purified product was subjected to recrystallization using hexane, thereby obtaining an aimed product. Yield weight: 3.23 g; yield by percentage: 50%; solid; melting point: 57 to 60 C.; 1H-NMR (60 MHz, CDCl3, delta): 3.75(3H, s), 6.26(1H, d, J=2 Hz), 6.75(1H, d, J=2 Hz), 7.0-7.6(4H, complex). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In 1,2-dimethoxyethane; for 3h;Heating / reflux; | Example 14 Preparation of 2-cyclopropyl-4-(3-trifluoromethylphenoxy)pyrimidine 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a cyclopropylcarbamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional cyclopropylcarbamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers / ethyl acetate: 20 / 1) to yield 2.1 g (75 percent) of the pure product having as a colorless liquid; 1H NMR (CDCl3); delta = 2.10 ppm (m, N=C(=N)-CH). |
2.1 g (75%) | With potassium carbonate; In 1,2-dimethoxyethane; | EXAMPLE 14 Preparation of 2-cyclopropyl-4-(3-trifluoromethylphenoxy)pyrimidine 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a cyclopropylcarbamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional cyclopropylcarbamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers/ethyl acetate: 20/1) to yield 2.1 g (75percent) of the pure product having as a colorless liquid; 1H NMR (CDCl3); delta=2.10 ppm (m, N=C(=N)-CH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
palladium diacetate; In water; ethyl acetate; toluene; | Example 9 A mixture of 5-(3-bromophenoxy)isophthalonitrile (75 mg), 3-hydroxybenzotrifluoride (61 mg), palladium(II) acetate (11 mg), tripotassium phosphate (0.106 g) and 2-(di-tert-butylphosphino)biphenyl (18 mg) in dry toluene was heated at reflux under a nitrogen atmosphere for 24 hours. Water and ethyl acetate were added to the cooled mixture, followed by acidification with aqueous hydrochloric acid (2M). The phases were separated and the organic layer dried over magnesium sulphate, concentrated and purified by flash chromatography. Elution with 5percent ethyl acetate/i-hexane gave 5-[3-(3-trifluoromethylphenoxy)phenoxy]isophthalonitrile (Compound 77, 32 mg), NMR 7.62 (1H, s); 7.52-7.37 (5H, m); 7.31 (1H, s); 7.25 (1H, d); 6.92 (1H, dd); 6.82 (1H, dd); 6.73 (1H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 19 Preparation Of 4-(alpha,alpha,alpha-Trifluoro-N-methyl-m-toluidino)-6-[(alpha,alpha,alpha-trifluoro-m-tolyl)oxy]pyrimidine 4,6-Dichloropyrimidine (1.55 g, 0.01mol) and <strong>[2026-70-2]N-methyl-3-trifluoromethylaniline</strong> (2.0 g, 0.llmol) are combined and heated to 126 C under N2for 1.5 hours. The resulting oil is taken up in ethyl acetate, is washed with 10% sodium carbonate and dried over sodium sulphate. The organic phase is concentrated under reduced pressure to yield a yellow oil which is purified by column chromatography to give 4-chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (1.78 g) as a white solid. 4-Chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (0.30 g, 0.001 mol.) and sodium carbonate (0.28g, 0.003 mol.) in DMF are stirred for 10 minutes. m-Trifluoro-methylphenol (0.16g, 0.001mol) is added and the mixture is heated to 60 C for 12 hours. The mixture is then cooled and poured into water. The product is extracted into ethyl acetate, washed with 10% sodium hydroxide, 10% hydrochloric acid, and 5% potassium carbonate, dried over Na2SO4, filtered, and is concentrated under reduced pressure. 6-(N-methyl-3-trifluoromethylanilino)-4-(3-trifluoromethylphenoxy)pyrimidine (0.16g) obtained by chromatography as a white solid. M.p. 118-119 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3,07 g (80%) | With potassium carbonate; In 1,2-dimethoxyethane; water; | EXAMPLE 11 Enhanced preparation of 4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine Water (20 mmoles) is added to a solution of 1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25 ml). The reaction mixture is stirred for 2 h under reflux. The resulting mixture is slowly added to a mixture consisting of a <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (60 mmoles) and dimethoxyethane (50 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein solution is completed additional <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (1 mmoles) is added. The reaction mixture is stirred for 2 hours under reflux and subsequently cooled down to ambient temperature, filtered through silica, and the organic phase is concentrated in vacuo. The residue is purified by chromatography on SiO2 (petrol ethers/diisopropylether: 6/1) to yield 3,07 g (80%) of the product having a melting point of 66-67 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Example 11 Enhanced preparation of 4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine Water (20 mmoles) is added to a solution of 1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25 ml). The reaction mixture is stirred for 2 h under reflux. The resulting mixture is slowly added to a mixture consisting of a <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (60 mmoles) and dimethoxyethane (50 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein solution is completed additional <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (1 mmoles) is added. The reaction mixture is stirred for 2 hours under reflux and subsequently cooled down to ambient temperature, filtered through silica, and the organic phase is concentrated in vacuo. The residue is purified by chromatography on SiO2 (petrol ethers / diisopropylether: 6 / 1) to yield 3,07 g (80 %) of the product having a melting point of 66-67 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | Example 21. Synthesis of 1-475-4. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (6-chloropyridin- 3-yl)methanol (10 g, 69.64 mmol, 1.00 equiv) in tetrahydrofuran (50 mL), 3- (trifluoromethyl)phenol (13.55 g, 83.59 mmol, 1.20 equiv), and triphenylphosphine (21.93 g, 83.61 mmol, 1.20 equiv). This was followed by the addition of DIAD (16.90 g, 83.58 mmol, 1.20 equiv) dropwise with stirring at 0C. The resulting solution was stirred overnight at room temperature. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/50-1/10). This resulted in 11.6 g (58%) of 2-chloro-5-((3- (trifluoromethyl)phenoxy)methyl)pyridine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; copper; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 4h;Inert atmosphere; | A mixture of <strong>[63927-22-0]8-bromoisoquinoline</strong> (1.0 g, 4.8 mmol) , 3- trifluoromethylphenol (1.55 g, 9.6 mmol), cesium carbonate is (3.9 g, 12 mmol) and dimethylsulfoxide (10 mL) was degassed with argon for 30 min, and to the mixture were added copper (I) iodide (0.91 g, 4.8 mmol), copper powder (0.30 g, 4.8 mmol) and 2, 2, 6, 6-tetramethyl-3, 5-heptanedione (0.49 mL, 2.5 mmol). Degassing was continued for additional 20 min. The resulting 20 mixture was heated at 100°C for 4 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and to the mixture were added water (50 mL) followed by 10percent aqueous sodium hydroxide solution' (50 mL) . The mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers 25 were washed with water (25 mL) and brine (50 mL) , and dried over sodium sulfate. The organic layer was concentrated under vacuum, and the residue was purified by combiflash with 8-12percent ethyl acetate in hexane as a mobile phase to give the title compound as an off-white solid (0.65 g., 47percent). MS(ESI)m/z: 30 290.1 ( +l) . 1H NMR (400 MHz, CDC13) : delta 7.11 (d, J = 7.2 Hz, 1H) ; 7.45 (dd, J= 1.6 & 7.6 Hz, 1H) ; 7 , 56-7.60 (m, 2H) ; 7.66- 7.70 (m, 1H) ; 7.73-7.81 (m, 2H) ; 7.92 (d, J = 5.6 Hz, 1H) ; 8.61 (bs, 1H) 9.51 (bs, 1H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 140℃; for 6.0h; | To 500mL three-necked flask equipped with a thermometer, was added DMF (200ml), between sequentially added trifluoromethylphenol (0.26mol, 42.2g), potassium carbonate (0.266mol, 37.2g), 2-chloro-6-carboxy pyridine (0.2mol, 31.6g), cuprous chloride (1.0 g of), heated to 140 deg.] C, the reaction 6.0H, cooled to room temperature, the reaction solution was poured into 600ml of ice water, pH = 3 adjusted with concentrated brine, and the precipitated solid was pumped was filtered off, washed with water, dried to obtain a white solid, yield: 75% |
75% | With potassium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 140℃; for 8.0h; | DMF (200 ml) was added to a 500 mL three-necked flask equipped with a thermometer, followed by the addition of m-trifluoromethylphenol.(0.26 mol, 42.2 g), potassium carbonate (0.266 mol, 37.2 g), 2-chloro-6-carboxypyridine (0.2 mol, 31.6 g) andCuprous chloride (1.0 g), warmed to 140 C, reacted for 8.0 h, cooled to room temperature, and poured into 600 ml of ice water.The pH of the brine was adjusted to 3, and the solid was precipitated, suction filtered, washed with water, and dried to give a white solid. Yield: 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With di-isopropyl azodicarboxylate; triphenylphosphine; In benzene; at 0℃;Reflux; | Diisopropyl azodicarboxylate (4.04 g, 20 mmol) was added into a cold (0 C.) solution of (3-(trifluoromethyl)phenol (1.62 g, 10 mmol)), <strong>[1147557-97-8]tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate</strong> (2.34 g, 11 mmol) and triphenylphosphine (5.24 g, 20 mmol) in anhydrous benzene (20 mL) The resulting mixture was refluxed overnight. Then, the mixture was concentrated and partitioned between EtOAc and water (1/1). The organic layer was washed with saturated NaHCO3 and brine. The organic extracts were dried over anhydrous NaSO4. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes:EtOAc 3/1 ratio) to afford tert-butyl 6-(3-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate as colorless oil (1.4 g, 40% yield); 1H NMR (400 MHz, CDCl3) delta ppm 7.36-7.34 (m, 1H), 7.20-7.18 (m, 1H), 6.99 (s, 1H), 6.95-6.92 (m, 1H), 4.61-4.57 (m, 1H), 3.99 (s, 2H), 3.93 (s, 2H), 2.75-2.70 (m, 2H), 2.37-2.32 (m, 2H), 1.43 (s, 9H). |
Tags: 98-17-9 synthesis path| 98-17-9 SDS| 98-17-9 COA| 98-17-9 purity| 98-17-9 application| 98-17-9 NMR| 98-17-9 COA| 98-17-9 structure
A114953 [349-58-6]
3,5-Bis(trifluoromethyl)phenol
Similarity: 0.98
A114953 [349-58-6]
3,5-Bis(trifluoromethyl)phenol
Similarity: 0.98
A114953 [349-58-6]
3,5-Bis(trifluoromethyl)phenol
Similarity: 0.98
A233289 [402-52-8]
1-Methoxy-4-(trifluoromethyl)benzene
Similarity: 0.91
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