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Product Details of Flecainide Impurity D

CAS No. :35480-52-5
Formula : C11H8F6O4
M.W : 318.17
SMILES Code : OC(=O)C1=C(OCC(F)(F)F)C=CC(OCC(F)(F)F)=C1
MDL No. :MFCD00221424
InChI Key :YPGYLCZBZKRYQJ-UHFFFAOYSA-N
Pubchem ID :2736078

Safety of Flecainide Impurity D

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of Flecainide Impurity D

* 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.

  • Upstream synthesis route of [ 35480-52-5 ]

[ 35480-52-5 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 75-89-8 ]
  • [ 35480-52-5 ]
YieldReaction ConditionsOperation in experiment
75.3%
Stage #1: With sodium t-butanolate In DMF (N,N-dimethyl-formamide) at 0 - 25℃; for 1 h;
Stage #2: at 100℃; for 10 h;
To a solution of 2,2,2-trifluoroethanol (14.7 g) and DMF (125 ml) was added sodium tert-butoxide (12.8 g) at 0° C.
The solution was stirred at 20 to 25° C. for 1 hour at which point 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (20 g) was added followed by cupric bromide (2.0 g).
The mixture was stirred at 100° C. for 10 hours, cooled to 10° C., and water (30 ml) was added followed by 20percent HCl solution (90 ml).
The solution was extracted with dichloromethane (3*80 ml), and the combined organic layers were washed with water (3*60 ml).
The solution was concentrated to one-third of the original volume and hexane (200 ml) was added.
The resulting suspension was stirred at room temperature for 2 hours, filtered and the damp cake was rinsed with hexane (2*40 ml).
The damp cake was dried in vacuo at 40° C. for 5 hours to give the product as a white solid (16.02 g, yield 75.3percent).
References: [1] Patent: US2005/59825, 2005, A1, . Location in patent: Page/Page column 4.
  • 2
  • [ 75-89-8 ]
  • [ 21739-92-4 ]
  • [ 35480-52-5 ]
YieldReaction ConditionsOperation in experiment
45% With potassium <i>tert</i>-butylate In tetrahydrofuran; water EXAMPLE 1
300 ml of THF are initially introduced at room temperature, and 84.7 g of potassium tert-butoxide are added with stirring 76.0 g of 2,2,2-trifluoroethanol are added dropwise to this reaction mixture, with the temperature being kept below 35° C.
When the addition is complete, stirring is continued, and 29.6 g of 5-bromo-2-chlorobenzoic acid are subsequently introduced.
After the subsequent addition of 27.3 g of copper(I) bromide, the reaction mixture is heated to reflux.
After 43 hours, the reaction mixture is cooled to 5° C. and allowed to run into dilute hydrochloric acid at 5° C.
The organic phase is separated from the aqueous phase,.
and the solvent is distilled off, during which the product precipitates.
100 ml of water are added to the residue and then filtered.
For purification, the crude product is taken up in MTB ether (methyl tert-butyl ether).
Undissolved components are separated off by filtration through neutral aluminium oxide, and the solvent is subsequently removed.
Recrystallisation from an ethanol/water mixture gives 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid in a yield of 45percent.
Melting point: 120-122° C., purity>98percent (HPLC).
References: [1] Patent: US2003/176721, 2003, A1, .
  • 3
  • [ 1023951-32-7 ]
  • [ 35480-52-5 ]
YieldReaction ConditionsOperation in experiment
81.6%
Stage #1: With pyridine; sodium hydroxide In water at 18 - 81℃; for 1 h;
Stage #2: With sodium permanganate In water at 81 - 93℃; for 7.75 h;
Stage #3: With hydrogenchloride In water
Example 2
Preparation of 2,5-bis(2,2,2-trifluorethoxy)benzoic acid (III)
The 2,5-bis(2,2,2-trifluoroethoxy)toluene (II) (220 g, 0.986 mol) was added to magnetically stirred pyridine (1550 mL) at 18-23°C.
The reaction mixture was stirred under a reflux.
Thereafter a 10 percent aqueous NaOH solution (20 mL, 0.050 mol) and copper (II) sulphate (0.27 g, 0.0017 mol) were added to the reaction mixture.
The reaction mixture was heated at 81 °C for 1 hour at which point a 40percent aqueous sodium permanganate solution (2290 g, 6.45 mol) was added in portions within a time period of 6.5 hours.
After the addition of an aqueous sodium permanganate solution the reaction mixture was stirred at 83 to 93°C for 75 minutes.
A precipitate of manganese oxides was separated by filtration at 80-95°C, the manganese oxides was rinsed on the filter with 5 liters of hot (80°C) water.
The combined filtrates were cooled to 9°C in 50 minutes.
The crystallization suspension was filtered to obtain damp cake of unreacted 2,5-bis(2,2,2-trifluoroethoxy)toluene (II), which was removed thereafter.
The filtrate of reaction mixture was mixed with activated charcoal (20.0 g) and stirred for 75 minutes; the precipitate of charcoal was separated by filtration and liquid phase was acidified to pH=1-2 using concentrated HCl.
The crystallization solution was filtrated and the product cake on the filter was rinsed with 200 mL of water.
The intermediate 2,5-bis(2,2,2-trifluorethoxy)benzoic acid (III) was dried at reduced pressure for 18 hours.
The 2,5-bis(2,2,2-trifluorethoxy)benzoic acid was obtained as an off-white powder (210.2 g, 81.6percent) having a melting point of 121°C to 125°C.
75.2%
Stage #1: With pyridine; sodium hydroxide; potassium permanganate In water at 85 - 100℃; for 1 h;
Stage #2: With hydrogenchloride In water
Example 3
Pyridine (310 mL), water (175 mL) and 2,5-bis(2,2,2-trifluoroethoxy)toluene (44.4 g, 0.154 mol) were mixed in a 1 liter round bottom flask, the pH was adjusted to 11-12 with sodium hydroxide.
The mixture was heated to 85°C and treated with potassium permanganate in 6 portions of 34 grams each, for a total of 204 g (1.29 mol).
The permanganate addition rate was such as to maintain the temperature at 90-100°C.
The reaction mixture was maintained at 85-95°C for an additional hour and filtered while hot.
The manganese oxide precipitate was washed with water and the washings were combined with the pyridine-water filtrate, then cooled to 5-10°C and filtered to remove the unreacted starting material.
The product was isolated by acidifying the filtrate with concentrated hydrochloric acid to pH=1-2 and removing the white precipitate by filtration.
After washing on the filter with water and drying under reduced pressure 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid was obtained as white powder in 37.2 g (0.116 mol, 75.2percent) yield having a melting point of 121°C to 125°C.
References: [1] Patent: EP1918280, 2008, A1, . Location in patent: Page/Page column 7.
[2] Patent: EP1918280, 2008, A1, . Location in patent: Page/Page column 4; 7.
  • 4
  • [ 35480-31-0 ]
  • [ 35480-52-5 ]
References: [1] British Journal of Pharmacology, 2016, p. 2446 - 2459.
  • 5
  • [ 106-37-6 ]
  • [ 35480-52-5 ]
References: [1] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2525 - 2537.
  • 6
  • [ 2150-46-1 ]
  • [ 35480-52-5 ]
References: [1] British Journal of Pharmacology, 2016, p. 2446 - 2459.
 

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