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Chemical Structure| 866615-03-4

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Product Details of [ 866615-03-4 ]

CAS No. :866615-03-4
Formula : C9H8F4O2
M.W : 224.15
SMILES Code : FC(C1=CC=C(F)C(OCOC)=C1)(F)F

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Application In Synthesis of [ 866615-03-4 ]

* 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 [ 866615-03-4 ]

[ 866615-03-4 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 107-30-2 ]
  • [ 141483-15-0 ]
  • [ 866615-03-4 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.75h;Inert atmosphere; To a solution of <strong>[141483-15-0]2-fluoro-5-(trifluoromethyl)phenol</strong> (2.0 g, 1 1 .1 mmol) in anhydrous dichloromethane (20 mL) under nitrogen atmosphere at 0C were successively added diisopropylethylamine (3.87 mL, 22.2 mmol) and chloromethyl methyl ether (1 .26 mL, 16.6 mmol). The mixture was stirred at 0C for 45 minutes before adding water (20 mL). Layers were separated and the aqueous one was extracted with dichloromethane (30 mL). The combined organic layers were washed with a 2 M sodium hydroxide solution (20 mL), dried over sodium sulfate and concentrated in vacuo to provide 1 -fluoro-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (34a) (2.49 g, 1 1 .1 mmol, 100%) as a lightly yellow oil.1 H NMR (400 MHz, CDCI3) 3.53 (s, 3H), 5.25 (s, 2H), 7.16-7.20 (m, 1 H), 7.24-7.27 (m, 1 H), 7.46 (dd, J = 1 .8 Hz, J = 7.4 Hz, 1 H).
100% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.75h;Inert atmosphere; Step 1: Preparation of intermediate 1-fluoro-2-(methoxymethoxy)-4-(trifluoro methyl)yenzene (1 a) To a solution of <strong>[141483-15-0]2-fluoro-5-(trifluoromethyl)phenol</strong> (2,0 g, 11.1 mmol) in anhydrous dichloromethane (20 mL) under nitrogen atmosphere at 0C were successively added diisopropylethylamine (3.87 mL, 22.2 mmol) and chloromethyl methyl ether (1.26 mL, 16.6 mmol). The mixture was stirred at 0C for 45 minutes before adding water (20 mL). Layers were separated and the aqueous one was extracted with dichloromethane (30 mL). The combined organic layers were washed with a 2 M sodium hydroxide solution (20 mL), dried over sodium sulfate and concentrated in vacuo to provide 1-fluoro-2-(methoxymethoxy)-4-(trifluoromethyl)yenzene (1a) (2.49 g, 11.1 mmol, 100%) as a lightly yellow oil. 1H NMR (400 MHz, CDCl3) delta 3.53 (s, 3H), 5.25 (s, 2H), 7.16-7.20 (m, 1H), 7.24-7.27 (m, 1H), 7.46 (dd, J= 1.8 Hz, J= 7.4 Hz, 1H).
100% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.75h;Inert atmosphere; To a solution of <strong>[141483-15-0]2-fluoro-5-(trifluoromethyl)phenol</strong> (2,0 g, 1 1 .1 mmol) in anhydrous dichloromethane (20 mL) under nitrogen atmosphere at 0C were successively added diisopropylethylamine (3.87 mL, 22.2 mmol) and chloromethyl methyl ether (1.26 mL, 16.6 mmol). The mixture was stirred at 0C for 45 minutes before adding water (20 mL). Layers were separated and the aqueous one was extracted with dichloromethane (30 mL). The combined organic layers were washed with a 2 M sodium hydroxide solution (20 mL), dried over sodium sulfate and concentrated in vacuo to provide 1 -fluoro-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (1a) (2.49 g, 1 1.1 mmol, 100%) as a lightly yellow oil. 1H NMR (400 MHz, CDCl3) delta 3.53 (s, 3H), 5.25 (s, 2H), 7.16-7.20 (m, 1 H), 7.24-7.27 (m, 1 H), 7.46 (dd, J = 1 .8 Hz, J = 7.4 Hz, 1 H).
100% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.75h;Inert atmosphere; Step 1: Preparation of intermediate 1-fluoro-2-(methoxymethoxy)-4-(trifluoro methyl)benzene (2a) To a solution of <strong>[141483-15-0]2-fluoro-5-(trifluoromethyl)phenol</strong> (2.0 g, 11.1 mmol) in anhydrous dichloromethane (20 mL) under nitrogen atmosphere at 0 C. were successively added diisopropylethylamine (3.87 mL, 22.2 mmol) and chloromethyl methyl ether (1.26 mL, 16.6 mmol). The mixture was stirred at 0 C. for 45 minutes before adding water (20 mL). Layers were separated and the aqueous one was extracted with dichloromethane (30 mL). The combined organic layers were washed with a 2 M sodium hydroxide solution (20 mL), dried over sodium sulfate and concentrated in vacuo to provide 1-fluoro-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (2a) (2.49 g, 11.1 mmol, 100%) as a lightly yellow oil. 1H NMR (400 MHz, CDCl3) delta 3.53 (s, 3H), 5.25 (s, 2H), 7.16-7.20 (m, 1H), 7.24-7.27 (m, 1H), 7.46 (dd, J=1.8 Hz, J=7.4 Hz, 1H).
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 5h; After 60 % sodium hydride (88 mg) was added into the DMF (5 ml) solution of <strong>[141483-15-0]4-fluoro-3-hydroxybenzotrifluoride</strong> (0.36 g), onto which chloromethyl methyl ether (0.24 g) was dropped with chilling on ice, the mixture was warmed to room temperature, and was then stirred for 5 hours. The mixture was poured into water, and was then subjected to extraction with ethyl acetate. Its organic layer was washed with brine, and was then dried with anhydrous magnesium sulfate. Its solvent was evaporated under reduced pressure to produce a crude chemical compound (11) (0.45 g), which was used for the next reaction.
60 % sodium hydride (1.77 g) was added to the DMF (75 ml) solution of <strong>[141483-15-0]4-fluoro-3-hydroxybenzotrifluoride</strong> (7.49 g) with chilling on ice. After its mixture was stirred for 30 minutes at room temperature, chloromethyl methyl ether (3.57 g) was dropped into it with chilling on ice. After the mixture was warmed to room temperature, and was then stirred for 30 minutes, it was further heated to 80 C, and was then stirred for 30 minutes. The chemical compound (29) (6.4 g) and 60 % sodium hydride (1.33 g) were added to the mixture at room temperature, and were then stirred for 30 minutes, they were heated to 100 C, and were then stirred for 3 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 a chemical compound (30) (6.3 g) and a chemical compound (31) (4.25 g). (0.56 g) was obtained. Chemical compound (30): Viscous oil 1H NMR (CDCl3) delta 1.43-1.60 (m,3H), 2.01-2.08 (m,4H), 2.36 (d,2H), 2.65-2.80 (m,1H), 3.02 (d,2H), 3.42 (s,2H), 3.53 (s,3H), 4.35 (brs,1H), 5.23 (s,2H), 6.93 (d,1H), 7.21-7.33 (m,8H) Chemical compound (31): Viscous oil 1H NMR (CDCl3) delta 1.46-1.55 (m,1H), 1.68-1.80 (m,2H), 1.91-1.97 (m,2H), 2.09 (brd, 3H), 2.68-2.82 (s plus m, 5H), 3.41 (s,2H), 3.54 (s,3H), 4.31 (t,1H), 5.22 (s,2H), 6.92 (d,1H), 7.20-7.33 (m,8H); Preparation Example 26 Preparation of 3alpha-[2-isopropylideneaminoxy-4-(trifluoromethyl)phenoxy]-8-[5-(trifluoromethyl)-2-pyridyl]-8-azabicyclo[3.2.1]octane (Chemical compound No. 2-212) Step 1 Preparation of 3alpha-[2-methoxymethoxy-4-(trifluoromethyl)phenoxy]-8-[5-(trifluoromethyl)-2-pyridyl]-8-azabicydo[3.2.1]octane (52) [Show Image] 60 % sodium hydride (0.59 g) was added, with chilling on ice, to the DMF (30 ml) solution of <strong>[141483-15-0]4-fluoro-3-hydroxybenzotrifluoride</strong> (2.48 g). After the mixture was stirred for 30 minutes at room temperature, chloromethyl methyl ether (1.18 g) was dropped into it with chilling on ice. After the mixture was warmed to room temperature, and was then stirred for 30 minutes, it was further heated to 80 C, and was then stirred for 30 minutes. After the chemical compound (19) (2.50 g) and 60 % sodium hydride (0.55 g) were added to the mixture at room temperature, and were then stirred for 30 minutes, they were heated to 100 C, and were then stirred for 2 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 (52) (3.98 g). mp. 69-73 C 1H NMR (CDCl3) delta 2.01-2.25 (m,6H), 2.37-2.44 (m,2H), 3.54 (s,3H), 4.57-4.63 (m,3H), 5.23 (s,2H), 6.56 (d,1H), 6.79 (d,1H), 7.23 (d,1H), 7.35 (s,1H), 7.61 (dd,1H), 8.41 (s,1H)
With N-ethyl-N,N-diisopropylamine; In dichloromethane; water; Step 1: Preparation of intermediate 1-fluoro-2-(methoxymethoxy)-4-(trifluoro methyl)benzene (2a) To a solution of <strong>[141483-15-0]2-fluoro-5-(trifluoromethyl)phenol</strong> (2,0 g, 11.1 mmol) in anhydrous dichloromethane (20 mL) under nitrogen atmosphere at 0C were successively added diisopropylethylamine (3.87 mL, 22.2 mmol) and chloromethyl methyl ether (1.26 mL, 16.6 mmol). The mixture was stirred at 0C for 45 minutes before adding water (20 mL). Layers were separated and the aqueous one was extracted with dichloromethane (30 mL). The combined organic layers were washed with a 2 M sodium hydroxide solution (20 mL), dried over sodium sulfate and concentrated in vacuo to provide 1-fluoro-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (2a) (2.49 g, 11.1 mmol, 100%) as a lightly yellow oil. 1H NMR (400 MHz, CDCl3) d 3.53 (s, 3H), 5.25 (s, 2H), 7.16-7.20 (m, 1H), 7.24-7.27 (m, 1 H), 7.46 (dd, J = 1.8 Hz, J = 7.4 Hz, 1 H).
6.88 g 1.6 g of 60% sodium hydride was added to 60 ml of the DMF solution containing 6.0 g of <strong>[141483-15-0]4-fluoro-3-hydroxybenzotrifluoride</strong> with ice-cooling. After stirring the mixture for 30 minutes at room temperature, 3.2 g of chloromethyl ether was added dropwise with ice-cooling. After reaching room temperature, the resulting mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. After being washed with water and dried with anhydrous magnesium sulfate, the organic layer was filtered and then vacuum-concentrated. The concentrate was purified by silica gel column chromatography (eluant: mixed solvent of n-hexane and ethyl acetate) to obtain 6.88 g of a compound (O).

 

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