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CAS No. : | 328-87-0 | MDL No. : | MFCD00019742 |
Formula : | C8H3ClF3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LCISFYAQKHOWBP-UHFFFAOYSA-N |
M.W : | 205.56 | Pubchem ID : | 67604 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 41.17 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.1 cm/s |
Log Po/w (iLOGP) : | 1.97 |
Log Po/w (XLOGP3) : | 3.46 |
Log Po/w (WLOGP) : | 4.38 |
Log Po/w (MLOGP) : | 3.08 |
Log Po/w (SILICOS-IT) : | 3.46 |
Consensus Log Po/w : | 3.27 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.57 |
Solubility : | 0.0553 mg/ml ; 0.000269 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.64 |
Solubility : | 0.047 mg/ml ; 0.000228 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.99 |
Solubility : | 0.0209 mg/ml ; 0.000102 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.88 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
With sodium methylate; In diethyl ether; ethanol; water; N,N-dimethyl-formamide; | Step A: Preparation of 2-(m-methylbenzylthio)-5-trifluoromethylbenzoic acid A mixture of m-methylbenzylmercaptan (3.36 g, 24.3 mmol), sodium methoxide (1.31 g, 24.3 mmol) and N,N-dimethylformamide (12.5 ml) was cooled to -15 C., and then added dropwise with stirring to a solution of <strong>[328-87-0]4-chloro-3-cyanobenzotrifluoride</strong> (5.0 g, 2.43 mmol), in N,N-dimethylformamide (7.5 ml). After stirring for 1 hour at room temperature under a nitrogen atmosphere, the mixture was added to cold water (175 ml) and extracted with chloroform. The organic extract was dried (sodium sulfate) and evaporated to give a pale yellow oil, which was taken up in ethanol (10 ml) and 20% aqueous sodium hydroxide (45 ml) and heated at reflux temperature for 24 hours. Concentration of the reaction mixture followed by diethyl ether extraction and evaporation gave an orange-red oil, that was suspended in water and acidified with 6N hydrochloric acid. The solid that separated out was filtered and dried by suction. The solid was recrystallized from diethyl ether; yield 5.95 g (75%). The 60 MHz NMR spectrum in chloroform-d was in accord with the desired structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Specific examples of the trifluoromethylbenzonitrile include 2-trifluoromethylbenzonitrile, 3-trifluoromethylbenzonitrile, 4-trifluoromethylbenzonitrile, 2-bromo-5-trifluoromethylbenzonitrile, 2-chloro-5-trifluoromethylbenzonitrile, 2-fluoro-5-trifluoromethylbenzonitrile, 4-iodo-2-trifluoromethylbenzonitrile, 4-iodo-3-trifluoromethylbenzonitrile, 2-methoxy-5-trifluoromethylbenzonitrile, ... | ||
Specific examples of the trifluoromethylbenzonitrile include 2-trifluoromethylbenzonitrile, 8-trifluoromethylbenzonitrile, 4-trifluoromethylbenzonitrile, 2-bromo-5-trifluoromethylbenzonitrile, 2-chloro 5-trifluoromethylbenzonitrile, 2-fluoro-5-trifluoromethylbenzonitrile, 4-iodo-2-trifluoromethylbenzonitrile, 4-iodo 3-trifluoromethylbenzonitrile, 2-methoxy-5-trifluoromethylbenzonitrile, 3-methoxy-4-trifluoromethylbenzonitrile, ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; at 110℃; | A flame-dried 500ml flask equipped with a magnetic stirring bar and a condenser was charged with 2- chloro-5-(trifluoromethyl)benzonitrile (15 g, 73 mmol), 5-isopropyl-2-methoxyphenylboronic acid (14.17 g, 73 mmol) , potassium fluoride (12.7 g, 219 mmol) and 1 ,4-dioxan (150 mL). The resulting mixture was purged with Nitrogen (N2). Tri-ferf-butylphosphine tetrafluoroborate adduct (2.12 g, 7.3 mmol) and tris(dibenzyllideneacetone)dipalladium(0) (3.34 g, 3.65 mmol) were added and the mixture was purged with N2 again. The mixture was then heated and stirred at 11O0C overnight. Solvent was removed in vacuo . The residue was partitioned between 1 M sodium hydroxide (200 mL) and diethyl ether (200 mL). The organic layer was collected and washed with saturated NaCI, dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure to give crude product as an oil. Purification by chromatography on silica gel (1-5% ethyl acetate in hexane) give the titled compound (23.2 g, 92%) as a clear oil.1H NMR (400 MHz, CHLOROFORM-D) § ppm 1.3 (d, J=7.0 Hz, 6 H) 2.9 (m, 1 H) 3.8 (s, 3 H) 7.0 (d, J=8.5 Hz, 1 H) 7.1 (d, J=2.5 Hz, 1 H) 7.3 (dd, J=8.5, 1.9 Hz, 1 H) 7.6 (d, J=8.3 Hz, 1 H) 7.9 (dd, J=8.2, 1.3 Hz, 1 H) 8.0 (d, J=2.1 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.47 g (39%) | EXAMPLE 9 8-Trifluoromethyl[1]benzothieno[2,3-b]pyrazine-2,3-(1H, 4H)-dione 2-Chloro-5-trifluoromethylbenzonitrile (5.0 g, 24.3 mmol) (Helv. chim. acta Vol. XLV, 2226 (1962)) was reacted with 3-mercaptopropionitrile and bromonitromethane following the procedure outlined in example 7 (Method K). Yield 2.47 g (39%) of 3-amino-2-nitro-5-trifluoromethylbenzo[b]thiophene. M.p. 198-201 C. 1H-NMR (DMSO-d6): delta7.95 (d, 1H), 8.13 (d, 1H), 8.86 (s, 1H), 8.4-9.4 (br. s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In N,N-dimethyl-formamide; | Step A: Preparation of 2-(p-methoxybenzylthio)-5-trifluoromethylbenzoic acid A solution of p-methoxybenzylmercaptan (20.0 g, 0.13 mol) and sodium methoxide (7.0 g) in N,N-dimethylformamide (55 ml) was added dropwise with stirring under a nitrogen atmosphere to a solution of <strong>[328-87-0]4-chloro-3-cyanobenzotrifluoride</strong> (26.7 g, 0.13 mol) in N,N-dimethylformamide (35 ml) cooled in an ice bath. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice-water and extracted several times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and evaporated to afford in essentially quantitative yield, 2-(4'-methoxybenzylthio)-5-trifluoromethylbenzonitrile as an oil; 60 MHZ NMR spectrum in chloroform-d was in accord with the desired structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium hydroxide; sodium hydroxide; sulfuric acid; In ethanol; water; | 2-Trifluoromethyl-6-methyl-9-thioxanthone A mixture of 40 grams of sodium hydroxide, 1 liter of ethanol and 124 grams of m-thiocresol was stirred until the sodium hydroxide was dissolved. 206 Grams of <strong>[328-87-0]2-chloro-5-trifluoromethylbenzonitrile</strong> were then added while stirring and under reflux. The mixture was then heated under reflux for two hours. After cooling 100 grams of potassium hydroxide were added and the mixture heated under reflux overnight. The mixture was then diluted with 3 liters of water and made acid with hydrochloric acid. The precipitate was filtered off and consisted of 2-(3-methylphenylthio)-5-trifluoromethylbenzoic acid. Yield: 240 grams. This was then treated with sulphuric acid as described for 2-methyl-6-fluoro-9-thioxanthone. The resulting substance consisted mainly of 2-trifluoro-6-methyl-9-thioxanthone with some 2-trifluoromethyl-8-methyl-9-thioxanthone. When boiling this mixture with acetone the more soluble 8-methyl-compound will go into solution. The remaining 2-trifluoromethyl-6-methyl-9-thioxanthone was obtained as a yellow crystalline substance, which melts at 174-178 degrees Centrigrade. Yield: 80 grams. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; water; | (a) Preparation of 3-(2-cyano-4-trifluoromethylphenoxy)benzoic acid 3-Hydroxybenzoic acid (27.6 g), 4-chloro-3-cyano-benzotrifluoride (41.1 g) and anhydrous potassium carbonate (55.2 g) were stirred together for 71/2 hours at 100 C. in dry dimethylformamide (500 ml) and then left at room temperature for 65 hours. The solvent was then removed under reduced pressure and the residue taken up in water and acidified with dilute hydrochloric acid. The solid which separated was washed with water, dissolved in ether and the solution dried and concentrated. The colourless solid which separated was recrystallized to give the benzoic acid derivative (24.0 g) with a melting point of 224-226 C. | |
With potassium carbonate; In N-methyl-acetamide; water; | (a) Preparation of 3-(2-cyano-4-trifluoromethylphenoxy)-benzoic acid 3-Hydroxybenzoic acid (27.6 g), <strong>[328-87-0]4-chloro-3-cyanobenzotrifluoride</strong> (41.1 g) and anhydrous potassium carbonate (55.2 g) were stirred together for 71/2 hours at 100 C. in dry dimethylformamide (500 ml) and then left at room temperature for 65 hours. The solvent was then removed under reduced pressure and the residue taken up in water and acidified with dilute hydrochloric acid. The solid which separated was washed with water, dissolved in ether and the solution dried and concentrated. The colourless solid which separated was recrystallized to give the benzoic acid derivative (24.0 g) with a melting point of 224-226 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium hydroxide; In sulfolane; methanol; | EXAMPLE 7 Preparation of 2-Cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether A solution of potassium hydroxide (2.6 g., 0.04 mole) 87.3% pure and 3-ethoxy-4-nitrophenol (7.3 g., 0.04 mole) in methanol (30 ml) is stripped to dryness under reduce pressure. A residue of potassium 3-ethoxy-4-nitrophenoxide is dissolved in sulfolane (200 g.) and 4-chloro-3-cyano-benzotrifluoride (8.2 g., 0.04 mole) is added. Gas-liquid chromotography shows the reaction to be complete after stirring at 110 C. for 41/2 hours and 135 C. for 21/2 hours. The reaction mixture is cooled and poured into deionized water and the precipitate which forms is filtered off and air dried. Recrystallization from isopropanol yields 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether (7.4 g. 53%) m.p. 143-145 C. |
53% | With potassium hydroxide; In sulfolane; methanol; | EXAMPLE 7 Preparation of 2-Cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether A solution of potassium hydroxide (2.6 g., 0.04 mole) 87.3% pure and 3-ethoxy-4-nitrophenol (7.3 g., 0.04 mole) in methanol (30 ml) is stripped to dryness under reduce pressure. A residue of potassium 3-ethoxy-4-nitrophenoxide is dissolved in sulfolane (200 g.) and 4-chloro-3-cyano-benzotrifluoride (8.2 g., 0.04 mole) is added. Gas-liquid chromotography shows the reaction to be complete after stirring at 110 C. for 41/2 hours and 135 C. for 21/2 hours. The reaction mixture is cooled and poured into de-ionized water and the precipitate which forms is filtered off and air dried. Recrystallization from isopropanol yields 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether (7.4 g. 53%) m.p. 143-145 C. |
53% | With potassium hydroxide; In sulfolane; methanol; | EXAMPLE 7 Preparation of 2-Cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether A solution of potassium hydroxide (2.6 g., 0.04 mole) 87.3% pure and 3-ethoxy-4-nitrophenol (7.3 g., 0.04 mole) in methanol (30 ml) is stripped to dryness under reduce pressure. A residue of potassium 3-ethoxy-4-nitrophenoxide is dissolved in sulfolane (200 g.) and 4-chloro-3-cyano-benzotrifluoride (8.2 g., 0.04 mole) is added. Gas-liquid chromatography shows the reaction to be complete after stirring at 110 C. for 41/2 hours and 135 C. for 21/2 hours. The reaction mixture is cooled and poured into deionized water and the precipitate which forms is filtered off and air dried. Recrystallization from isopropanol yields 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether (7.4 g. 53%) m.p. 143-145 C. |
53% | With potassium hydroxide; In sulfolane; methanol; | EXAMPLE 7 Preparation of 2-Cyano-alpha,alpha,alpha -trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether A solution of potassium hydroxide (2.6 g., 0.04 mole) 87.3% pure and 3-ethoxy-4-nitrophenol (7.3 g., 0.04 mole) in methanol (30 ml) is stripped to dryness under reduce pressure. A residue of potassium 3-ethoxy-4-nitrophenoxide is dissolved in sulfolane (200 g.) and 4-chloro-3-cyano-benzotrifluoride (8.2 g., 0.04 mole) is added. Gas-liquid chromotography shows the reaction to be complete after stirring at 110 C. for 41/2 hours and 135 C. for 21/2hours. The reaction mixture is cooled and poured into deionized water and the precipitate which forms is filtered off and air dried. Recrystallization from isopropanol yields 2-cyano-alpha,alpha,alpha -trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether (7.4 g. 53%) m.p. 143-145 C. |
53% | With potassium hydroxide; In sulfolane; methanol; | EXAMPLE 7 Preparation of 2-Cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether A solution of potassium hydroxide (2.6 g., 0.04 mole) 87.3% pure and 3-ethoxy-4-nitrophenol (7.3 g., 0.04 mole) in methanol (30 ml) is stripped to dryness under reduce pressure. A residue of potassium 3-ethoxy-4-nitrophenoxide is dissolved in sulfolane (200 g.) and 4-chloro-3-cyano-benzotrifluoride (8.2 g., 0.04 mole) is added. Gas-liquid chromotography shows the reaction to be complete after stirring at 110 C. for 41/2 hours and 135 C for 21/2 hours. The reaction mixture is cooled and poured into deionized water and the precipitate which forms is filtered off and air dried. Recrystallization from isopropanol yields 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether (7.4 g. 53%) m.p. 143-145 C. |
53% | With potassium hydroxide; In sulfolane; methanol; | EXAMPLE 7 Preparation of 2-Cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether A solution of potassium hydroxide (2.6 g., 0.04 mole) 87.3% pure and 3-ethoxy-4-nitrophenol (7.3 g., 0.04 mole) in methanol (30 ml) is stripped to dryness under reduce pressure. A residue of potassium 3-ethoxy-4-nitrophenoxide is dissolved in sulfolane (200 g.) and 4-chloro-3-cyano-benzotrifluoride (8.2 g., 0.04 mole) is added. Gas-liquid chromotography shows the reaction to be complete after stirring at 110 C for 41/2 hours and 135 C for 21/2 hours. The reaction mixture is cooled and poured into deionized water and the precipitate which forms is filtered off and air dried. Recrystallization from isopropanol yields 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-3-ethoxy-4-nitrophenyl ether (7.4 g. 53%) m.p. 143-145 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium hydroxide;adams Copper; In N-methyl-acetamide; ethanol; water; | 162 grams of 92% sodium ethanolate were dissolved in 750 milliliters of dimethylformamide and 260 grams of 3-fluorophenol, 530 grams of <strong>[328-87-0]2-chloro-5-trifluoromethylbenzonitrile</strong>, 25 grams of Adams Copper catalyst and 25 grams of cuprus iodide were added. The mixture was heated to 150 C without reflux condenser, whereupon a reflux condenser was placed in a neck of the flask and heating was continued for 3 hours at 160C. Dimethylformamide was distilled off in vacuum. The residue was suspended in water and extracted with chloroform, the chloroform-layer separated, washed with water, filtered and evaporated. The residue was dissolved in 1500 milliliters of 96% ethanol and 500 milliliters of water, whereupon 530 grams of potassium hydroxide were added in small portions and the mixture refluxed for 18 hours. 700 milliliters of concentrated hydrochloric acid were added dropwise and ethanol evaporated, whereupon the mixture was cooled and extracted with 2000 milliliters of ether. The ether phase was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum. The residue consisted of 2-(3-fluorophenyloxy)-5-trifluoromethyl-benzoic acid as an oil. Yield: 700 grams. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With potassium hydroxide; In thiophene; methanol; | EXAMPLE 3 Preparation of 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-4-chlorophenylether A solution of potassium hydroxide (1.96 g., 0.03 mole, 86.2% pure) and p-chlorophenol (3.86 g., 0.03 mole) in methanol (20 ml.) is stripped under reduced pressure. The residue is dissolved in sulpholane (60 ml), 4-chloro-3-cyano-alpha,alpha,alpha-trifluorotoluene (6.17 g., 0.03 mole) added, and the resulting solution heated at 120 -130C for 5 hours. After cooling, the solution is pured into water and the precipitate filtered off, washed with water, and recrystallized from pentane/isopropanol to give 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-4-chlorophenylether (3.3g., 37%) m.p. 87.5 -89C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrogen; sodium ethanolate; In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; | EXAMPLE I Into 100 ml. of ethanol is added 12.4 g. (0.10 moles) of benzylmercaptan. While nitrogen is bubbled into the solution, 100 ml. of a 1 molar sodium ethoxide in ethanol solution is added. The solvent is evaporated and 100 ml. of anhydrous dimethylformamide is added to the crude solid sodium mercaptide. To the resulting solution is then added 21 g. (0.10 moles) of <strong>[328-87-0]4-chloro-3-cyanobenzotrifluoride</strong>. The reaction mixture is stirred under nitrogen at room temperature for 1/2 hour and then poured into about 800 ml. of ice-water. After stirring this mixture for 5 minutes, it is extracted with four 200 ml.-portions of ether. The extracts are combined, dried over anhydrous sodium sulfate and evaporated to provide, after drying under high vacuum, a pale yellow oil that crystallizes to a solid upon standing. The yield of crude 2-benzylthio-5-trifluoromethylbenzonitrile is 27.4 g. (94 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dimethyl sulfate; In nitrobenzene; butan-1-ol; | Example 7 A solution of 10.05 g. of 3-amino-5-trifluoromethylindazole in 120 ml. of dry nitrobenzene is treated with 4.75 ml. of dimethyl sulfate by dropwise addition over five minutes. The resulting mixture is stirred at 150 C. for one hour, then cooled to room temperature and taken up in excess dilute hydrochloric acid. The acid solution is neutralized with 40% sodium hydroxide and solid sodium bicarbonate. A solid forms which is filtered, washed with hot benzene and recrystallized from ethanol and ethanol-heptane to give 1(or 2)-methyl-3-amino-5-trifluoromethylindazole, M.P. 225-226 C. An ethyl acetate solution of the free base is treated with an equivalent amount of citric acid to give, upon concentration and cooling, the citrate salt. A mixture of 10.0 g. of <strong>[328-87-0]2-chloro-5-trifluoromethylbenzonitrile</strong> and 5.0 ml. of monomethylhydrazine in 50 ml. of butanol is heated at reflux for 18 hours. The mixture is evaporated to dryness. The residue is slurried with ether and filtered. The yellow crystalline solid is 1(or 2)-methyl-3-amino-5-trifluoromethylindazole, M.P. 145 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzyl alcohol; In water; dimethyl sulfoxide; | EXAMPLE 4 2-Benzyloxy-5-trifluoromethylbenzoic Acid To a solution of 10.8 g. (0.1 mole) of benzyl alcohol in 50 ml. of dimethylsulfoxide is added 4.2 g. (0.1 mole) of a 56.6% suspension of sodium hydride in oil, and the mixture stirred until the evolution of hydrogen ceases. 4-Chloro-3-cyanobenzotrifluoride (18.6 g.; 0.09 mole) is added and the resulting mixture heated 3-4 hours at steam bath temperatures. The reaction is cooled, diluted with 200 ml. of water and the resulting precipitate filtered and dried. The intermediate, 4-benzyloxy-3-cyanobenzotrifluoride, is recrystallized from isopropanol, 10.8 g., m.p. 69-70.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 28 2-Methoxy-5-trifluoromethylbenzoic Acid Starting with 4-chloro-3-cyanobenzotrifluoride and sodium methoxide and following the procedure of Example 4, the above product is prepared, m.p. 105-106.5 C. Netherlands Application 6,507,712 (C.A., 64, 12606g) reports a melting point of 103-105 C. for this compound. In a similar manner are prepared 2-methoxy-3-trifluoromethylbenzoic acid and 3-trifluoromethyl-4-methoxybenzoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In N-methyl-acetamide; ethanol; water; | EXAMPLE 13 2-Methylthio-5-trifluoromethylbenzoic Acid Into 75 ml. of dimethylformamide containing 20 ml. of 5N sodium hydroxide solution is bubbled methyl mercaptan until a weight increase of 6.3 g. (~30% excess) is noted, followed by the addition of 20.5 g. (0.1 mole) of <strong>[328-87-0]4-chloro-3-cyanobenzotrifluoride</strong>. After allowing the reaction mixture to stir at room temperature for 2 hours, the precipitated solid is filtered and the filtrate diluted with 500 ml. of water and extracted with ether. The ether layer is separated, dried over sodium sulfate and concentrated to a semi-solid which on trituration with hexane provides the desired intermediate, 4-methylthio-3-cyanobenzotrifluoride, as a crystalline solid, 15.2 g., m.p. 68-72 C. Thirteen grams of the above intermediate in 150 ml. of ethanol containing 200 ml. of 20% aqueous sodium hydroxide solution is heated at 90 C. for 18 hours. The reaction mixture is cooled and acidified with 12N hydrochloric acid, and the resulting precipitate filtered and dried, 14.2 g., m.p. 198-200 C. A small sample is sublimed at125-135 C. and 0.02 mm pressure, m.p. 198.5-200 C. Anal. Calcd. for C9 H7 O2 SF3: C, 45.76; H, 2.99. Found: C, 46.09; H, 3.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethylene glycol dimethyl ether; | EXAMPLE 6 2,4-diamino-6-(3-trifluoromethyl-6-chlorophenyl)-s-triazine 4.0 g of 3-cyano-4-chlorobenzotrifluoride (90-102 C./29 mm Hg), 2.0 g of dicyanodiamide and 1.0 g of caustic potash are refluxed in 10 ml of diglyme for 3 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from methanol. Melting point: 210-212 C.; yield: 3.8 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-methoxy-ethanol; | EXAMPLE 7 2,4-diamino-6-(3-trifluoromethyl-6-methoxyethoxyphenyl)-s-triazine 6.3 g of 3-cyano-4-chlorobenzotrifluoride, 3.1 g of dicyanodiamide and 1.0 g of caustic potash are refluxed in 10 ml of methyl cellosolve for 5 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from methanol. Melting point: 224-226 C.; yield: 4.3 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; water; | 104 grams of 3-fluorothiophenol and 50 grams of sodium ethanate were dissolved in 500 milliliters of 99% ethanol whereupon 165 grams of <strong>[328-87-0]5-trifluoromethyl-2-chlorobenzonitrile</strong> were added and the mixture refluxed for 4 hours. Then 165 grams of potassium hydroxide and 30 milliliters of water were added and the refluxing continued for 4 hours. The reaction mixture was dissolved in 4 liters of water and the solution made acid with concentrated hydrochloric acid; filtered, and the filter cake washed and dried in a desiccator. Yield: 250 grams of 2-(3'-fluorophenylthio)-5-trifluoromethyl-benzoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium hydroxide; In sulfolane; methanol; | Preparation of 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-4-nitro phenyl ether A solution of potassium hydroxide (3.2 g. 0.05 mole of 89.3% purity) and p-nitrophenol (7.0 g. 0.05 mole) in methanol (25 ml.) is stripped under reduced pressure. The residue is dissolved in sulfolane, 4-chloro-3-cyano alpha,alpha,alpha-trifluorotoluene (10.3 g. 0.05 mole) added, and the resulting solution heated at 150 C for 5 hours. After cooling, the solution is diluted with benzene (350 ml.) washed with water (6 * 250 ml.), dried, and the solvent removed. The residue (12.5 g.) is recrystallized from isopropanol to give 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-4-nitrophenyl ether (7.6 g., 49%) m.p. 93-98 C. |
49% | With potassium hydroxide; In sulfolane; methanol; | EXAMPLE 1 Preparation of 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-4-nitro phenyl ether A solution of potassium hydroxide (3.2 g. 0.05 mole of 89.3% purity) and p-nitrophenol (7.0 g. 0.05 mole) in methanol (25 ml.) is stripped under reduced pressure. The residue is dissolved in sulfolane, 4-chloro-3-cyano alpha,alpha,alpha-trifluorotoluene (10.3 g. 0.05 mole) added, and the resulting solution heated at 150 C. for 5 hours. After cooling, the solution is diluted with benzene (350 ml.) washed with water (6*250 ml.), dried, and the solvent removed. The residue (12.5 g.) is recrystallized from isopropanol to give 2-cyano-alpha,alpha,alpha-trifluoro-p-tolyl-4-nitrophenyl ether (7.6 g., 49%) m.p. 93-98 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; hydroquinone; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dimethyl sulfoxide; | EXAMPLE 3 2'-Cyano-4'-trifluoromethyl-4-hydroxydiphenyl ether 12.1 g (0.11 mole) of hydroquinone and 11.85 g (0.18 mole) of pulverised potassium hydroxide are dissolved in 70 ml of dimethylsulphoxide, and the solution is heated in a nitrogen atmosphere to 90 C. and subsequently stirred for 30 minutes at this temperature. There is then added dropwise in the course of 30 minutes a solution of 20.55 g (0.1 mole) of <strong>[328-87-0]2-cyano-4-trifluoromethylchlorobenzene</strong> in 30 ml of dimethylsulphoxide. After completion of the addition, stirring is maintained at 90 C. for one hour. The cooled solution is then poured into 300 ml of ice-water, and neutralised with concentrated sulphuric hydrochloric acid, whereupon 2'-cyano-4'-trifluoromethyl-4-hydroxydiphenyl ether precipitates in crystalline form. The product is separated by filtration and dried at 50 C. in vacuo. There is thus obtained 25.5 g (97% of theory) of 2'-cyano-4'-trifluoromethyl-4-hydroxydiphenyl ether, m.p. 130-132 C. The following hydroxydiphenyl ethers of the formula I are produced in an analogous manner. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; benzyl alcohol; In diethyl ether; ethanol; water; | Sodium hydride powder (0.08 g) was added to dry benzyl alcohol (15 ml) and the mixture was warmed in order to complete the resulting reaction. The mixture was then treated with <strong>[328-87-0]2-chloro-5-trifluoromethylbenzonitrile</strong> (0.62 g) and was heated, with stirring, at between 90 and 95 C. for 20 hours. The mixture was then diluted with benzyl alcohol (10 ml), the mixture was filtered, and the filtrate was evaporated under vacuum. The resulting oil was then treated with a solution of sodium hydroxide (6 g) in aqueous ethanol (95%; 30 ml) and heated at reflux. The solvent was removed in vacuo, water (25 ml) and diethyl ether (25 ml) were added to the residue, the mixture was agitated and the layers were separated. The aqueous layer was then acidified by treatment with concentrated hydrochloric acid. The precipitate was filtered off and recrystallized from water to give 2-benzyloxy-5-trifluoromethylbenzoic acid (0.35 g), m.p. 94-95 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 100℃; for 20h; | PREPARATION 50 4'-amino-3'-fluoro-4-(trifluoromethyl)-2-biphenylcarbonitrile A solution of 4-BOC-amino-3-fluorophenylboronic acid (2.76 mmol), <strong>[328-87-0]2-chloro-5-(trifluoromethyl)benzonitrile</strong> (1.84 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane adduct (0.06 mmol), and cesium carbonate (9.2 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) was heated at 100 C. for 20 h. The reaction mixture was cooled, poured into brine (50 mL), and extracted with (3*50 mL) ethyl acetate. The combined organic layers were dried over magnesium sulfate and decolorizing charcoal, filtered through Celite, and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded the protected intermediate as a pale orange solid. This solid was treated with a solution of dichloromethane (10 mL) and trifluoroacetic acid (4 mL) and stirred for 2 h. Concentration in vacuo and subsequent neutralization afforded the title product as a pale tan solid (36%). ESMS [M+H]+: 281.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen sulfide; ammonia; In ethanol; at 0 - 20℃; for 1h; | To a solution of 2-chloro-5-(trifIuoromethyl)benzonitrile (1.03g, delta.Ommol) in 2M NH3 in EtOH (10.OmL) at O 0C was introduced a gentle stream of H2S gas. Upon saturation a yellow solution was observed. The reaction mixture was sealed and stirred at room temperature for 1 hour. Excess H2S gas was removed by purging the reaction mixture with a steady stream of N2 gas. The solvent was removed under reduced pressure to give 2-chloro-5-(trifluoromethyl)benzothioamide in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 % sodium hydride (0.71 g) was added, with chilling on ice, to the DMF (30 ml) solution of the chemical compound (19) (3.69 g). After the mixture was stirred at room temperature for 30 minutes, <strong>[328-87-0]4-chloro-3-cyanobenzotrifluoride</strong> (2.78 g) was added to it. After the mixture was stirred for 30 minutes at room temperature, it was further heated to 100 C, and was then stirred for 4 hours. After the mixture was cooled to room temperature, it was poured into water, and was then subjected to extraction with ethyl acetate. After its organic layer was washed with water, and was then dried with anhydrous magnesium sulfate, it was filtered, and was then concentrated under reduced pressure. Its residue was purified by column chromatography to produce the chemical compound mentioned in the above title (56) (4.24 g). mp. 110-113 C 1H NMR (CDCl3) delta 2.01-2.45 (m,8H), 4.60 (brs, 2H), 4.74 (t,1H), 6.59 (d,1H), 6.91 (d,1H), 7.63 (dd,1H), 7.77 (dd,1H), 7.86 (s,1H), 8.41 (s,1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 36 2-(2-(2-Chloro-5-(trifluoromethyl)phenyl)oxazol-4-yl)acetic acid[0106] <strong>[328-87-0]2-chloro-5-trifluoromethyl-benzonitrile</strong> (550 mg 2.68 mmol) was dissolved in 4N NaOH (3 mL) and THF (6 mL) and heated at 60 0C overnight. Upon completion, the reaction was cooled to ambient temperature and diluted with 10% citric acid. The aqueous layer was extracted with EtOAc, washed with 10% citric acid (2x) and brine, dried over MgSO4, concentrated under reduced pressure and purified via silica gel chromatography (3:2 Hexanes/EtOAc). The resulting 2-chloro-5-trifluoromethyl-benzamide (100 mg, 0.447 mmol) was reacted with methyl-4-chloroacetoacetate (300 mg, 1.34 mmol) according to the synthesis described in example 4. The methyl ester was saponified as described in the synthesis of example 2. The organic layer residue was dissolved in DMSO, and the product purified from the reaction mixture via preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 35℃; for 24h;Inert atmosphere; | K2CO3 (3.32 g, 24 mmol) is dissolved in water (20 mL) and the resulting solution is degassed by sparging with argon gas for 10 min. (2-chloro-5-(trifluoromethyl)phenyl) methanol (COK) (2.94 g, 14 mmol), and boranic acid METB (2.78 g, 14 mmol) dissolved in THF (20 mL) are added to the K2CO3 solution. The resulting solution is degassed by sparging with argon gas for 15 min. The catalyst, 1,1 bis(di-tertbutylphosphino)ferrocene palladium dichloride (75 mg, 0.8 mol%) is added. The organic layer turns dark brown immediately. The biphasic mixture is aged at 35 C with vigorous stirring for 24 hours. The mixture is cooled to rt and water (80) is added, followed by DIPE (80 mL) and the aqueous layer is removed. The organic layer was washed with 1 M NaOH (aq) (50 mL), 1 M HCl (aq) (50 mL) and water (50 mL), dried over Na2SO4, and filtered through silica gel pot The solvent is removed under reduced pressure to yield EBFOH as a brownish solid (4.18 g, 91%):'H NMR (CDCl3) delta 1.22 (t, J = 7.6, 3H), 1.95 (t, J= 6.2,1H), 2.64 (q, J =7.5, 2H), 4.49 (bs, 2H), 6.69 (d, J =11.6, 1H), 6.96 (d, J = 8.7, 1H), 7.29 (d, J = 7.9, 1H), 7.58 (d, J = 7.9, 1H), 7.85 (s, 1H). |
40% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 20 - 45℃; for 32h;Inert atmosphere;Product distribution / selectivity; | A 3 M K2CO3 solution is prepared by adding solid K2CO3 (31 g, 0.22 mol) to water (100 mL). Cooling is applied to keep the solution at 20-25 C. (2-chloro-5-(trifluoromethyl)phenyl)methanol (Formula VI', X = Cl, R1 = CH2OH) (17.5 g, 84 mmol), and <strong>[875446-29-0]4-fluoro-5-isopropyl-2-methoxyphenylboronic acid</strong> (MIPB) (18.1 g, 85 mmol) are added to the K2C03 followed by all THF (100 mL) rinse. The solution is degassed by sparging with argon gas for 20 min. The catalyst, 1,1-bis(di-tertbutylphosphino)ferrocene palladium dichloride (300 mg, 0.55 mol%) is added. The organic layer turns dark brown immediately. The biphasic mixture is aged at 35-45 C with vigorous stirring for 32 hours. The mixture is cooled to r. t. and water (150 mL) is added, followed by petrol ether (150 mL) and the aqueous layer is removed. The organic layer was washed with water (2×200 mL) and filtered through silica gel and the solvent is removed under reduced pressure to yield brownish oil which is crystallized from heptane to give 4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl)methanol as a pale white solid (28.5 g, 80%). mp 93,5-95,5 C; 1H NMR (CDCl3) delta 1.24 (d, J = 6.9 Hz, 6H), 1.95 (t, J = 6.1 Hz, 1H), 3.21 (sept., J = 6.9 Hz, 1H), 3.73 (s, 3H), 4.49 (m, 2H), 6.68 (d, J = 12.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.59 (dd, J1 = 8.0 Hz, J2 =1.3 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula VII1 and VII2 are prepared and listed in Table 1 and Table 2, respectively. |
40% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In tetrahydrofuran; water; at 20 - 45℃; for 32h;Inert atmosphere; | General procedure: A 3 M K2CO3 solution is prepared by adding solid K2C03 (31 g, 0.22 mol) to water (100 mL). Cooling is applied to keep the solution at 20-25 C. (2-chloro-5-(trifluoromethyl)phenyl)methanol (Formula VI', X = CI, Ri = CH2OH) (17.5 g, 84 mmol), and <strong>[875446-29-0]4-fluoro-5-isopropyl-2-methoxyphenylboronic acid</strong> (MIPB) (18.1 g, 85 mmol) are added to the K2CO3 followed by all THF (100 mL) rinse. The solution is degassed by sparging with argon gas for 20 min. The catalyst, 1 , 1-bis(di-tertbutylphosphino)ferrocene palladium dichloride (300 mg, 0.55 mol%) is added. The organic layer turns dark brown immediately. The biphasic mixture is aged at 35-45 C with vigorous stirring for 32 hours. The mixture is cooled to r. t. and water (150 mL) is added, followed by petrol ether (150 mL) and the aqueous layer is removed. The organic layer was washed with water (2x200 mL) and filtered through silica gel and the solvent is removed under reduced pressure to yield brownish oil which is crystallized from heptane to give 4'-fluoro-5'-isopropyl-2'-methoxy-4-(tnfluoromethyl)biphenyl-2-yl)methanol as a pale white solid (28.5 g, 80%). mp 93.5-95.5 C; 1H NMR (CDC ) C 1 .24 (d, J = 6.9 Hz, 6H), 1.95 (t, J = 6.1 Hz, 1 H), 3.21 (sept., J = 6.9 Hz, 1 H), 3.73 (S, 3H), 4.49 (m, 2H), 6.68 (d, J = 12.0 Hz, 1 H), 6 99 (d, J = 8.6 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 1 H), 7.59 (dd, J, = 8.0 Hz, J2 = 1 .3 Hz, 1 H), 7.86 (d, J = 0.7 Hz, 1 H). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula VII1 and Vll2 are prepared and listed in Table 1 and Table 2, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 20 - 45℃; for 32h;Inert atmosphere;Product distribution / selectivity; | A 3 M K2CO3 solution is prepared by adding solid K2CO3 (31 g, 0.22 mol) to water (100 mL). Cooling is applied to keep the solution at 20-25 C. (2-chloro-5-(trifluoromethyl)phenyl)methanol (Formula VI', X = Cl, R1 = CH2OH) (17.5 g, 84 mmol), and 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid (MIPB) (18.1 g, 85 mmol) are added to the K2C03 followed by all THF (100 mL) rinse. The solution is degassed by sparging with argon gas for 20 min. The catalyst, 1,1-bis(di-tertbutylphosphino)ferrocene palladium dichloride (300 mg, 0.55 mol%) is added. The organic layer turns dark brown immediately. The biphasic mixture is aged at 35-45 C with vigorous stirring for 32 hours. The mixture is cooled to r. t. and water (150 mL) is added, followed by petrol ether (150 mL) and the aqueous layer is removed. The organic layer was washed with water (2×200 mL) and filtered through silica gel and the solvent is removed under reduced pressure to yield brownish oil which is crystallized from heptane to give 4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl)methanol as a pale white solid (28.5 g, 80%). mp 93,5-95,5 C; 1H NMR (CDCl3) delta 1.24 (d, J = 6.9 Hz, 6H), 1.95 (t, J = 6.1 Hz, 1H), 3.21 (sept., J = 6.9 Hz, 1H), 3.73 (s, 3H), 4.49 (m, 2H), 6.68 (d, J = 12.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.59 (dd, J1 = 8.0 Hz, J2 =1.3 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula VII1 and VII2 are prepared and listed in Table 1 and Table 2, respectively. |
80% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In tetrahydrofuran; water; at 20 - 45℃; for 32h;Inert atmosphere; | General procedure: A 3 M K2CO3 solution is prepared by adding solid K2C03 (31 g, 0.22 mol) to water (100 mL). Cooling is applied to keep the solution at 20-25 C. (2-chloro-5-(trifluoromethyl)phenyl)methanol (Formula VI', X = CI, Ri = CH2OH) (17.5 g, 84 mmol), and 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid (MIPB) (18.1 g, 85 mmol) are added to the K2CO3 followed by all THF (100 mL) rinse. The solution is degassed by sparging with argon gas for 20 min. The catalyst, 1 , 1-bis(di-tertbutylphosphino)ferrocene palladium dichloride (300 mg, 0.55 mol%) is added. The organic layer turns dark brown immediately. The biphasic mixture is aged at 35-45 C with vigorous stirring for 32 hours. The mixture is cooled to r. t. and water (150 mL) is added, followed by petrol ether (150 mL) and the aqueous layer is removed. The organic layer was washed with water (2x200 mL) and filtered through silica gel and the solvent is removed under reduced pressure to yield brownish oil which is crystallized from heptane to give 4'-fluoro-5'-isopropyl-2'-methoxy-4-(tnfluoromethyl)biphenyl-2-yl)methanol as a pale white solid (28.5 g, 80%). mp 93.5-95.5 C; 1H NMR (CDC ) C 1 .24 (d, J = 6.9 Hz, 6H), 1.95 (t, J = 6.1 Hz, 1 H), 3.21 (sept., J = 6.9 Hz, 1 H), 3.73 (S, 3H), 4.49 (m, 2H), 6.68 (d, J = 12.0 Hz, 1 H), 6 99 (d, J = 8.6 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 1 H), 7.59 (dd, J, = 8.0 Hz, J2 = 1 .3 Hz, 1 H), 7.86 (d, J = 0.7 Hz, 1 H). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula VII1 and Vll2 are prepared and listed in Table 1 and Table 2, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | General procedure: A 500 mL dry flask was charged with 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP) (24.60 g, 0.10 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri- isopropylborate (32 mL, 0.1 mol) was added. The mixture was cooled to -80 C. Then 2.5 n-BuLi in hexanes (48 mL, 0.12 mol) was added slowly, maintaining a temperature below -55C. After completion of the n-BuLi addition, the reaction mixture was slowly warmed (1 hour) to -10C and water (120 mL) was added, followed by commercially available 2-bromo-5-(trifluoromethyl)benzonitrile (Formula VI', X = Br, R2 = CN) (25.00 g, 0.10 mmol) and the catalyst, 1 , 1 bis( di-tertbutylphosphino)ferrocene palladium dichloride (265 mg, 0.8 mol%) addition. The organic layer turns dark brown immediately. The biphasic mixture is aged at room temperature with vigorous stirring for 12 hours. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (aq) (100 mL), water (300 mL) and filtered through silica gel. The solvent was removed under reduced pressure to yield brown oil which was crystallized from EtOH/water (300/100 mL). The resulting slurry was filtered and the filter cake was washed with cold 50% EtOH. The product was dried at 40 C under vacuum to yield 4'-fluoro-5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Formula VII', Ri = CN, R2 = isopropyl) as a pale white solid (25.20 g, 75%). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula Vlh and Vll2 are prepared and listed in Table 3 and Table 4, respectively. For NMR data and melting points see Table 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: A 500 mL dry flask was charged with 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP) (24.60 g, 0.10 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri- isopropylborate (32 mL, 0.1 mol) was added. The mixture was cooled to -80 C. Then 2.5 n-BuLi in hexanes (48 mL, 0.12 mol) was added slowly, maintaining a temperature below -55C. After completion of the n-BuLi addition, the reaction mixture was slowly warmed (1 hour) to -10C and water (120 mL) was added, followed by commercially available 2-bromo-5-(trifluoromethyl)benzonitrile (Formula VI', X = Br, R2 = CN) (25.00 g, 0.10 mmol) and the catalyst, 1 , 1 bis( di-tertbutylphosphino)ferrocene palladium dichloride (265 mg, 0.8 mol%) addition. The organic layer turns dark brown immediately. The biphasic mixture is aged at room temperature with vigorous stirring for 12 hours. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (aq) (100 mL), water (300 mL) and filtered through silica gel. The solvent was removed under reduced pressure to yield brown oil which was crystallized from EtOH/water (300/100 mL). The resulting slurry was filtered and the filter cake was washed with cold 50% EtOH. The product was dried at 40 C under vacuum to yield 4'-fluoro-5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Formula VII', Ri = CN, R2 = isopropyl) as a pale white solid (25.20 g, 75%). According to the same procedure in various scales and different concentrations of catalyst some other biaryl of Formula Vlh and Vll2 are prepared and listed in Table 3 and Table 4, respectively. For NMR data and melting points see Table 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 75 - 100℃; for 8.08333h;Inert atmosphere; | General procedure: A solution of 2 M Na2CO3 (10 mL) was added under nitrogen to a 2-bromoaniline (10 mmol) in 60 mL dioxane. After 5 min stirring at 75 C, Pd[P(C6H5)3]4 was added followed by (10 mmol) of a 2-cyanophenylboronic acid pinacol ester. The reaction was stirred 8 h at 100 C. After cooling to rt the mixture was vacuum concentrated to half of its initial volume and extracted with CH2Cl2 (30 mL) and water (30 mL). The aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The solid crystallized upon concentration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.57 g | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h; | A mixture of 15.0 g of 2-chioro-5-trifluoromethyl- benzonitrile, 7.10 g of methyl thioglycolate, 9.70 g of potassium carbonate, and 100 ml of N,N-dimethylformamide was stirred for 8 hours at 60 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 9.57 g of methyl 3-amino-5-trifluoromethylbenzo [b]thiophene-2-carboxylate (hereinafier, described as a ?compound 133 of the present invention?). ?H-NMR (CDC13) oe: 7.91 (s, -H), 7.86-7.84 (m, 1H), 7.69-7.67 (m, 1H), 5.96 (br s, 2H), 3.91 (s, 3H). |
9.57 g | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h; | A mixture of 15.0 g of <strong>[328-87-0]2-chloro-5-trifluoromethylbenzonitrile</strong>, 7.10 g of methyl thioglycolate, 9.70 g of potassiumcarbonate, and 100 ml of N,N-dimethylformamide was stirred for 8 hours at 60C. After the reaction mixture was cooledto room temperature, water was added thereto, and extraction was performed three times by using tert-butyl methylether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining9.57 g of methyl 3-amino-5-trifluoromethylbenzo[b]thiophene-2-carboxylate. |
Tags: 328-87-0 synthesis path| 328-87-0 SDS| 328-87-0 COA| 328-87-0 purity| 328-87-0 application| 328-87-0 NMR| 328-87-0 COA| 328-87-0 structure
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Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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