2-fluoro-6-methoxyphenol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 2-bromo-5-chloro-3-nitropyridine (2.37 g, 10 mmol) was dissolved in 40 mL DMF was added of 2-methoxyl-6-fluorophenol (1.7 g 11.9 mmol) was added into the solution followed by potassium carbonate (2.76, 20 mmol). The mixture was stirred at room temperature for 5 h, then poured into ice water (200 mL). The precipitate was filtered and dried under high vacuum to provide 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-3-nitro-pyridine. was added into the solution The precipitate was filtered dried under high vacuum

反応条件: temp:98.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 250 mL pressure resistant vial which contained a mixture of 2-fluoro-6-methoxy-phenol (1000 mg, 7 mmole), 1-iodo-3-nitro-benzene (2500 mg, 10 mmole), Cs2CO3 (1200 mg, 7 mmole) and N,N-dimethylglycine.HCl (200 mg, 1.5 mmole) in dioxane (40 mL) was added CuI (140 mg, 0.7 mmole) at rt. The reaction mixture was bumbled with Ar for 5 min at rt and then the vial was sealed. The reaction mixture was stirred and heated to 98° C. for 5 d. After cooling to rt, the reaction mixture was poured into 250 mL ice-water which was extracted with ethyl acetate (3×50 mL), washed with water (2×50 mL), brine (50 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by silica gel column chromatography with ethyl acetate/hexane as eluent to give 1450 mg (75% yield) of product (10). the vial was sealed After cooling to rt was extracted with ethyl acetate (3×50 mL) washed with water (2×50 mL), brine (50 mL) dried over Na2SO4 After removal of solvent the residue was purified by silica gel column chromatography with ethyl acetate/hexane as eluent

反応条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 2-fluoro-6-methoxy phenol (1) (2.8 g, 20 mmol), N,N-dimethyl glycine.HCl (837 mg, 6 mmol), Cs2CO3 (13 g, 40 mmol), 1-fluoro-4-iodobenzene (2.3 mL, 20 mmol), in Dioxane (40 ml) was added copper iodone (381 mg, 2 mmol). The reaction mixture was stirred at 105° C. over 1 week. Upon heating the reaction mixture turned from brown to a bright green. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in-vacuo. The crude was purified by silica gel eluted with hexane/EtOAc (10:1), concentrated in-vacuo, to provide 300 g (21% yield) of product (2). Upon heating the reaction mixture After cooling to room temperature the reaction mixture was filtered the filtrate was concentrated in-vacuo The crude was purified by silica gel eluted with hexane/EtOAc (10:1) concentrated in-vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a heated solution (80° C.) of hexamethylenetetramine (2.8 g, 20 mmol) in trifluoroacetic acid (10 mL) was added dropwise over a 50 minutes period 2-fluoro-6-methoxyphenol (1.42 g, 10 mmol) in trifluoroacetic acid (10 mL). The mixture was heated for an additional 1 hour, concentrated and water (50 ml) was added. The solution was stirred for 10 minutes and solid potassium carbonate was added until the solution was neutral. The solid that formed was collected to afford 1.1 g of 2-fluoro-3-hydroxy-4-methoxybenzaldehyde (65%). 1H NMR (500 MHz; DMSO-d6): δ3.90 (s, 3H); 6.98 (d, J=8.5 Hz, 1H); 7.31 (t, J=8.5 Hz, 1H); 9.66 (br, 1H); 10.02 (s, 1H). The mixture was heated for an additional 1 hour concentrated water (50 ml) was added solid potassium carbonate was added until the solution The solid that formed was collected

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,5-Dichloro-4-(2-fluoro-6-methoxy-phenoxy)-pyrimidine was prepared from 2-Fluoro-6-methoxy-phenol and 2,4,5-Trichloropyrimidine in an analogous manner to Example 1230a. (1.95 g, 96%) LCMS 290 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 7.38-7.34 (m, 1H), 7.10-7.03 (m, 2H), 3.80 (s, 3H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared starting from 2-fluoro-6-methoxyphenol (178 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.17 mmol; prepared in Example 52, Step 2) to give 230 mg (66%) of a yellow oil. HRMS m/z calcd for C17H21FN4O3 (M)+ 348.1598, found 348.1602.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The intermediate benzylcyanide compound of the formula 12 above, according to the present invention, may be prepared by converting a 2-fluoro-6-methoxyphenol compound of the formula 13 ##STR11## under aminomethylation conditions, with formaldehyde and N,N-dimethylamine, into the N,N-dimethyl-4-hydroxy-3-methoxy-5-fluorobenzylamine compound of the formula 14 ##STR12## The benzylamine compound of the formula 14, by treatment with methyliodide and displacement with NaCN, is converted into the 3-methoxy-4-hydroxy-5-fluorobenzylnitrile compound of formula 15 ##STR13## The benzylnitrile compound of the formula 15 is treated with BBr3, followed by dibenzylation of the catechol 3,4-dihydroxy-5-fluorobenzylcyanide compound of the formula 16 ##STR14## with benzylchloride to give the 3,4-dibenzyloxy-5-fluorobenzylcyanide compound of the formula 12 ##STR15## may be prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-(2-Fluoro-6-methoxy-phenoxy)-3-nitrobenzaldehyde (1.0 g, 70%) was prepared from 2-fluoro-6-methoxyphenol (0.78 g, 5.5 mmol) and 4-fluoro-3-nitrobenzaldehyde (0.84 g, 5.0 mmol) following the general procedure A. This was reduced to 5-formyl-2-(2-fluoro-6-methoxy-phenoxy)-aniline (0.57 g, 62%) following general procedure B. 1-[2-(2-Fluoro-6-methoxy-phenoxy)-5-formyl-phenyl]-3-thiazol-2-yl-urea (265 mg, 69%) was prepared from 5-formyl-2-(2-fluoro-6-methoxy-phenoxy)-aniline (261 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-(2-fluoro-6-methoxyphenoxy)-nitrotoluene (0.9 g, 65%) was prepared from 2-fluoro-6-methoxyphenol (0.78 g, 5.5 mmol) and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure A. This compound was reduced to 4-fluoro-2-(2-fluoro-6-methoxyphenoxy)aniline (0.58 g, 72%) following the general procedure C. 1-[2-(2-Fluoro-6-methoxy-phenoxy)-4-methyl-phenyl]-3-thiazol-2-yl-urea (122 mg, 65%) was prepared from 2-(2-fluoro-6-methoxy-phenoxy)-4-methyl-aniline (124 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-(2-fluoro-6-methoxyphenoxy)-nitrotoluene (0.9 g, 65%) was prepared from 2-fluoro-6-methoxyphenol (0.78 g, 5.5 mmol) and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure A. This compound was reduced to 4-fluoro-2-(2-fluoro-6-methoxyphenoxy)aniline (0.58 g, 72%) following the general procedure C. 1-[2-(2-Fluoro-6-methoxy-phenoxy)-4-methyl-phenyl]-3-thiazol-2-yl-urea (122 mg, 65%) was prepared from 2-(2-fluoro-6-methoxy-phenoxy)-4-methyl-aniline (124 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-fluoro-2-(2-fluoro-6-methoxyphenoxy)benzoate (0.88 g, 60%) was prepared from methyl 2,3-difluorobenzoate (0.86 g, 5 mmol) and 2-fluoro-6-methoxyphenol (0.78 g, 5.5 mmol) as described in procedure A. Hydrolysis of this ester with LiOH in aqueous methanol furnished 2-(2-methoxy-6-fluorophenoxy)-3-fluorobenzoic acid (0.86 g, 90%). To a solution of 3-fluoro-2-(2-fluoro-6-methoxyphenoxy)benzoic acid (0.56 g, 2.0 mmol) in 1,2-dichloroethane (10 ml) was added oxalyl chloride (0.18 ml, 2.2 mmol). The solution was stirred at room temperature for 45 min. To this solution was added NaN3 (390 mg, 6 mmol) and the mixture was heated to reflux for 3 h. 2-Aminothiazole (200 mg, 2 mmol) was then added to this mixture and was further refluxed for 3 h. The mixture was concentrated and the residue was purified by column chromatography (silica, CH2Cl2 then 10% ethyl acetate in CH2Cl2) to afford 1-[3-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]-3-(thiazol-2-yl)urea in (414 mg, 55%).