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CAS No. : | 29632-74-4 | MDL No. : | MFCD00011738 |
Formula : | C6H5FIN | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | CUMTUBVTKOYYOU-UHFFFAOYSA-N |
M.W : | 237.01 | Pubchem ID : | 185694 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
94% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 160℃; under 4500.45 - 5250.53 Torr; for 2h;Microwave irradiation; | General procedure: Microwave-assisted Ullmann-Goldberg coupling of 1.0 equivalent of the corresponding lactams(compound 1-4) with 1.2 equiv. of 2-fluor-4-iodoaniline (5), 0.5 equiv. of CuI (except for compound 1where 2 equivalents of catalyst were used), 2 equivalents of N,N’-dimethlyethylenediamine (DMEDA),and 2 equivalents of K3PO4 in 3.5 mL of dry toluene. The reaction mixture was irradiated in a microwaveoven with 6-7 bar, 850 watts for 2 h at 160 C (except for compound 7, where 90 C was used).The resulting solution was passed through a pad of silica and Celite with ethyl acetate and thecrude mixture was purified by flash column chromatography (silica gel, n-hexane/AcOEt, 5:5) [80]. |
74% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane;Reflux; Inert atmosphere; | Under argon, a suspension of 29.6 g (125 mmol) of 2-fluoro-4-iodoaniline, 15.8 g (156 mmol, 1.25 eq.) of <strong>[109-11-5]morpholin-3-one</strong> [J.-M. Lehn, F. Montavon, Helv. Chim. Acta 1976, 59, 1566-1583], 9.5 g (50 mmol, 0.4 eq.) of copper(I) iodide, 53.1 g (250 mmol, 2 eq.) of potassium phosphate and 8.0 ml (75 mmol, 0.6 eq.) of N,N'-dimethylethylenediamine in 300 ml of dioxane is stirred under reflux overnight. After cooling to RT, the reaction mixture is filtered through a layer of kieselguhr, and the residue is washed with dioxane. The combined filtrates are concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel 60, dichloromethane/methanol 100:1→100:3). This gives 24 g (74% of theory) of the title compound. LC-MS (method 4): Rt=0.87 min; MS (ESIpos): m/z=211 [M+H]+; 1H-NMR (500 MHz, DMSO-d6): δ=7.05 (dd, 1H), 6.87 (dd, 1H), 6.74 (dd, 1H), 5.14 (s, 2H), 4.11 (s, 2H), 3.92 (dd, 2H), 3.63 (dd, 2H). |
74% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane;Reflux; Inert atmosphere; | Method 2:Under argon, a suspension of 29.6 g (125 mmol) of 2-fluoro-4-iodoaniline, 15.8 g (156 mmol, 1.25 eq.) of <strong>[109-11-5]morpholin-3-one</strong> [J.-M. Lehn, F. Montavon, Helv. Chim. Acta 1976, 59, 1566-1583], 9.5 g (50 mmol, 0.4 eq.) of copper(I) iodide, 53.1 g (250 mmol, 2 eq.) of potassium phosphate and 8.0 ml (75 mmol, 0.6 eq.) of N,N'-dimethylethylenediamine in 300 ml of dioxane was stirred under reflux overnight. After cooling to RT, the reaction mixture was filtered through a layer of kieselguhr and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, dichloromethane/methanol 100:1→100:3). This gave 24 g (74% of theory) of the title compound.LC-MS (Method 3): Rt=0.87 min;MS (ESIpos): m/z=211 [M+H]+;1H-NMR (500 MHz, DMSO-d6): δ=7.05 (dd, 1H), 6.87 (dd, 1H), 6.74 (dd, 1H), 5.14 (s, 2H), 4.11 (s, 2H), 3.92 (dd, 2H), 3.63 (dd, 2H). |
33% | With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In toluene; at 140℃; for 2h;microwave; | 2.0 g (8.4 mmol) 2-fluoro-4-iodo-aniline, 860 mg (8.5 mmol) <strong>[109-11-5]morpholin-3-one</strong>, 162 mg (0.86 mmol) copper(I)iodide, 2.33 g (16.86 mmol) potassium carbonate and 91 μl N,N'-dimethylethylenediamine are suspended in 18 ml of toluene under an argon atmosphere and stirred for two hours in a microwave at a power of 35 Watts at 140 C. Water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol 50:1). Yield: 590 mg (33%) Rf value: 0.60 (silica gel; dichloromethane/methanol 9:1) C10H11FN2O2 (210.21) Mass spectrum: (M+H)+=211 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 12h; | Example 1:; 5-FIuoro-3-(2-fluoro-4-iodo-phenylamino)-pyridine-2-carbonitrile; To solution of 2-fluoro-4-iodoaniline (930.5 mg, 3.93 mmol) and 3,5-difluoropyridine- 2-carbonitrile (500 mg, 3.57 mmol) in THF (8 mL) at -78°C, was added LiHMDS (6.1 ml, 7.50 mmol). The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture as diluted with ethyl acetate and washed with H2O and brine. The <n="35"/>organic layer was dried with solid Na2SO4 and was concentrated. The resulting residue was purified by flash chromatography in silica (25percent ethyl acetate-hexane) to give pure product. LC/MS [7.72 min; 358 (M+l)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.35% | B: Preparation of the 3. 4-DIFLUORO-2- (2-FLUORO-4-IODO-PHENYLAMINO)-5-NITRO-BENZOIC acid A stirred solution of 2,3, 4-trifluoro-5-nitrobenzoic acid (400 g, 1.9 mol) in dry THF (6L) under nitrogen was cooled to-58 C and a solution of 2.0 L 1.0 M LIHMDS (1. OU, 2L, 2.0 mol) was added dropwise at-58 C. This reaction mixture (yellow solution turned into yellow orange suspension) was designated as reaction mixture A. In a separate reaction flask, 2-FLUORO-4-IODOANILINE (400G, 1.0 mol) in THF (4L) was cooled TO-58 C under nitrogen and a solution LIHMDS (1. 0M, 3.65L, 3.6 mol) was added dropwise AT-58 C (the yellow solution turned into a white suspension). This reaction mixture was designated as mixture B. Both the reaction mixtures A and B were stirred for 45 min. , maintaining the temperature AT-58 C and mixture A was transferred into reaction mixture B by a canula. The resulting orange suspension was stirred for 1 h AT-58 C, then allowed to warm-up to room temperature and stirred overnight under nitrogen. The reaction mixture was cooled to - 10 C and adjusted to pH 1 by bubbling HCI gas. The white solid separated was filtered through a short bed of CELITE, washed with THF (3L) and the filtrate (brown) was evaporated under vacuum. The residue (yellow orange solid) obtained was triturated with 10% aq. HCI (3L) solution and the solid separated was filtered, washed with 10% aq HCI (2X1L), water (4 X 1.0 L) and the wet solid was taken in toluene (1 L). The toluene solution was evaporated to remove water and the residue obtained was digested in hot methanol (3.0 L), filtered, washed with methanol (2L) then dried to give the title compound as solid (yellow). Yield: 543. 9G (55. 35%). | |
[00130] Step B: 3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-5-nitrobenzoic acid:[ 00131] To a solution of 2-fluoro-4-iodoaniline (2.9 g, 11.8 mmoles) in 50 ml anhydrous THF at -60 C, 40 ml of a 1M solution of LHMDS in THF (40 mmoles) is added dropwise. In a separate flask, 2,3,4-trifluoro-5- nitrobenzoic acid (5 g, 22.6 mmoles), previously dissolved in THF (50 ml), is treated, at -60 C, with 25 ml of a 1M solution of LHMDS in THF (25 mmoles). Both solutions are stirred at -78 C for 45 min and the second solution is transferred via cannula to the first reaction mixture. After completion of the addition the resulting mixture is stirred under argon at room temperature for 15 hours. The reaction mixture is quenched with water, then 1N HCl is added (pH = 0-1) followed by brine (100 ml). The crude material is extracted with THF (3 x 100 ml), the organic layers are combined and dried (Na2SO4) and the solvent is removed to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 11:; 6-fluoro-2-[(2-fluoro-4-iodophenyl)amino]nicotinic acid; To solution of 2-fluoro-4-iodoaniline (0.82 g, 3.46 mmol) in THF (1OmL) at -780C LiHMDS (6.00 mL, 6.60 mmol) was added. After stirring for 15 min, 2,6- difluoronicotinic acid (0.50 g, 3.14 mmol) was added to the mixture. The mixture was allowed to warm to room temperature until completion. The mixture was washed with NaOH (1 N) and extracted with ether. The aqueous layer was acidified with concentrated HCl and back-extracted with ethyl acetate. The organic layer was concentrated to afford product. Second crop of product was obtained by purifying the THF/ether layer with silica gel chromatography. LC/MS [Method B: rt. 9.09 min, m/z 377 (M+l)]. |