2-(2-Fluoro-4-iodoanilino)-3,4-difluorobenzoic Aci

Off-White Solid

A solution of 2, 3, 4-uorobenzoic acid (1.35 g, 7.68 mmol), 2-uoro-4-iodoaniline (1.91 g, 8.06 mmol), and lithium amide (0.702 g, 30.6 mmol) in tetrahydrofuran (10.5 ml) was reacted using a standardmethod (Cai et al., 2008) to give 3, 4-diuoro-2-((2-uoro-4-iodo-phenyl)amino)benzoic acid (A 2A R PAM-1, 2.99 g, 99percent) as a brown solid(Figure S1); IR (KBr) 3311, 1673, 1602, 1520, 1500, 1444, 1273, 768 cm−1;1H NMR (400 MHz CD 3 OD) δ = 7.89 (1 H, ddd, J = 2.3, 6.0, 9.2 Hz), 7.48 (1 H, dd, J = 1.8, 10.5 Hz), 7.41 (1 H, ddd, J = 1.4, 1.8, 8.5 Hz), 6.91 (1 H, ddd, J = 7.3, 9.4, 9.4 Hz), 6.75 (1 H, ddd, J = 5.6, 8.5, 8.5 Hz);13C NMR (100 MHz acetone-d 6 ) δ = 169.9, 155.7 (dd, J C, F = 252.1, 4.8 Hz), 155.6 (d, J C, F = 252.1 Hz), 143.6 (dd, J C, F = 247.8, 14.9 Hz), 137.4 (dd, J C, F = 7.7, 2.9 Hz), 135.0 (d, J C, F = 3.8 Hz), 131.9(d, J C, F = 11.5 Hz), 129.8 (dd, J C, F = 9.6, 3.8 Hz), 125.8 (d, J C, F = 21.0 Hz), 123.8 (d, J C, F = 5.8 Hz), 116.4, 110.1 (d, J C, F = 18.2 Hz), 84.7 (d, J C, F = 6.7 Hz); HRMS-ESI: m/z [M-H]-calcdfor C13H6F3INO2, 391.9395; measured, 391.9414.Example 2.TO a stirred suspension of 2, 3, 4-trifluorobenzoic acid (78g, 0.44 moles) in dry THE (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained BELOW-67C. A dark orange solution was formed and this was stirred for another 20 minutes AT-67C. The mixture was designated as Solution A. To a stirred solution of 2-fluoro-4-iodoaniline (105g, 0.44 moles, Aldrich) in dry THF (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained below- 67C. The dark brown suspension was stirred for an additional 30 minutes at- 67C. The mixture was designated as Solution B. Solution A was transferred to solution B via a cannula under positive nitrogen pressure at-65C at such a rate to keep the temperature BELOW-55C. Then the mixture was slowly warmed to RT and stirred overnight. The reaction mixture was quenched with dry HC1 in diethyl ether (1.5 L, freshly prepared, PH-1-2. The solution was filtered through a layer of Celite. The filtrate was washed with aq. HC1 (2M, 2XLL), brine and dried. Solvent was removed under reduced pressure to give a solid, which was suspended in hexanes-acetone (9: 1, v/v, 150 mL) and stirred for 30 minutes. 3, 4- dufluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid was obtained by filtration as a white solid (135g, 78percent, mp. 195-197C).Example 2B.3, 4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (SC-1-148 Acid) [0020] A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (73; 2.38 g, 10.05 mmol), 2, 3, 4-trifluorobenzoic acid, (74; 1.8 g, 10.225 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0° C. and LiNHA 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (38; 2.38 g, 10.0 mmol), 2, 3, 4-trifluorobenzoic acid, (37; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 °C and LiNHA 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (26; 2.38 g, 10.0 mmol), 2, 3, 4-trifluorobenzoic acid, (25; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 Example 3. Preparation of N-((R)-2.3-dihvdroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound 1) 3, 4-Difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (20 g, 0.051 mol) in 100 mL acetonitrile was treated with 1, 1'-carbonyldiimidazole (CDI) (8.66 g, 0.053 mol) (Aldrich, Cat No. 11, 553-3) and stirred for about 2 hours at 20-25C until the reaction was deemed complete by HPLC (Conditions D). 94 mL (84.9 g) of 9.7% w/w solution of O-{[(4R)-2, 2-dimethyl-1, 3-dioxolan-4-yl]methyl}hydroxylamine (6) in toluene was then added and stirred for about 4 hours or until the reaction was deemed complete by HPLC (Conditions D). To this mixture was added 66 mL of 5.6 % hydrochloric acid solution, and after stirring, the bottom aqueous phase was discarded. Again 66 mL of 5.6 % hydrochloric acid solution was added to the organic phase and stirred at 20-25C for 12-18 hours or until the reaction was deemed complete by HPLC (Conditions D). The bottom layer was then discarded and the remaining organic layer was concentrated under reduced pressure to remove about 10-20% solvent, and the volume was adjusted to about 9-11 mL/g with toluene (80 mL). Crude product was then crystallized at 10-15C. The slurry was allowed to stir for about 2 hours and the crude solid product was filtered, and dried. The dried crude product was recharged to the reactor and dissolved into 150 mL of 5% v/v ethanol/toluene mixture at 55- 67C. The solution was then clarified at this temperature through filter (line filter) to remove any remaining particulate matter. The solution was then cooled slowly to 5C to crystallize and stirred for at least 2 h, filtered and dried. The dried solid product was redissolved in EtOH (60 mL) at 35C, and product was precipitated out by adding water (300 mL) at 35C followed by cooling to 200C. The slurry was stirred for at least 2 hours to transform the crystals to the desired polymorphic Form IV as determined by DSC and Powder X-ray Diffraction pattern (PXRD). The slurry was filtered and dried under vacuum oven at 70- 90C to yield the final N-((R)-2, 3-dihydroxypropoxy)-3, 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I) product. Overall chemical yield was 13 g, 53%. Melting point (DSC): 112+1 C. Appearance: White to off-white crystals.Shown in Figure 1, PXRD conforms to polymorphic crystal Form IV disclosed in the above mentioned U.S. Patent Application No. 10/969, 681 EPO A solution of 2, 3, 4-uorobenzoic acid (1.35 g, 7.68 mmol), 2-uoro-4-iodoaniline (1.91 g, 8.06 mmol), and lithium amide (0.702 g, 30.6 mmol) in tetrahydrofuran (10.5 ml) was reacted using a standardmethod (Cai et al., 2008) to give 3, 4-diuoro-2-((2-uoro-4-iodo-phenyl)amino)benzoic acid (A 2A R PAM-1, 2.99 g, 99%) as a brown solid(Figure S1); IR (KBr) 3311, 1673, 1602, 1520, 1500, 1444, 1273, 768 cm-1;1H NMR (400 MHz CD 3 OD) delta = 7.89 (1 H, ddd, J = 2.3, 6.0, 9.2 Hz), 7.48 (1 H, dd, J = 1.8, 10.5 Hz), 7.41 (1 H, ddd, J = 1.4, 1.8, 8.5 Hz), 6.91 (1 H, ddd, J = 7.3, 9.4, 9.4 Hz), 6.75 (1 H, ddd, J = 5.6, 8.5, 8.5 Hz);13C NMR (100 MHz acetone-d 6 ) delta = 169.9, 155.7 (dd, J C, F = 252.1, 4.8 Hz), 155.6 (d, J C, F = 252.1 Hz), 143.6 (dd, J C, F = 247.8, 14.9 Hz), 137.4 (dd, J C, F = 7.7, 2.9 Hz), 135.0 (d, J C, F = 3.8 Hz), 131.9(d, J C, F = 11.5 Hz), 129.8 (dd, J C, F = 9.6, 3.8 Hz), 125.8 (d, J C, F = 21.0 Hz), 123.8 (d, J C, F = 5.8 Hz), 116.4, 110.1 (d, J C, F = 18.2 Hz), 84.7 (d, J C, F = 6.7 Hz); HRMS-ESI: m/z [M-H]-calcdfor C13H6F3INO2, 391.9395; measured, 391.9414.Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) A solution of 2-fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich, Catalog No. 30, 660-6) and 2, 3, 4- trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich, Cat No. 33, 382-4) in 38 mL tetrahydrofuran (THF) was prepared and a portion (about 5%) of this solution was added to a stirring slurry of lithium amide (5 g, 0.22 mol) in 40 mL THF at 50-55 C. After about 15-30 min. an exotherm followed by gas release and color change are observed. The remaining portion of the (8) and (7) solution was added slowly over 1-2 hr while maintaining temperatures within 45-55C. The mixture was stirred until the reaction was deemed complete (by HPLC (Conditions C). The final mixture was then cooled to 20-25C and transferred to another reactor containing 6 N hydrochloric acid (47 mL) followed by 25 mL acetonitrile, stirred, and the bottom aqueous phase was discarded after treatment with 40 mL 50% sodium hydroxide solution. The organic phase was concentrated under reduced pressure and 57 mL acetone was added. The mixture was heated to 50C, stirred, and added with 25 mL warm (40-50C) water and cooled to 25-30C to allow crystallization to occur (within 1-4 hours). Once the crystallization occurred, the mixture was further cooled to 0 to -5C and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in vacuum oven at about 55C. Overall chemical yield was 21.4 g, 80%. EPO TO a stirred suspension of 2, 3, 4-trifluorobenzoic acid (78g, 0.44 moles) in dry THE (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained BELOW-67C. A dark orange solution was formed and this was stirred for another 20 minutes AT-67C. The mixture was designated as Solution A. To a stirred solution of 2-fluoro-4-iodoaniline (105g, 0.44 moles, Aldrich) in dry THF (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained below- 67C. The dark brown suspension was stirred for an additional 30 minutes at- 67C. The mixture was designated as Solution B. Solution A was transferred to solution B via a cannula under positive nitrogen pressure at-65C at such a rate to keep the temperature BELOW-55C. Then the mixture was slowly warmed to RT and stirred overnight. The reaction mixture was quenched with dry HC1 in diethyl ether (1.5 L, freshly prepared, PH-1-2. The solution was filtered through a layer of Celite. The filtrate was washed with aq. HC1 (2M, 2XLL), brine and dried. Solvent was removed under reduced pressure to give a solid, which was suspended in hexanes-acetone (9: 1, v/v, 150 mL) and stirred for 30 minutes. 3, 4- dufluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid was obtained by filtration as a white solid (135g, 78%, mp. 195-197C).Example 2B. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide method To a stirring solution of 2, 3, 4-trifluorobenzoic acid (13) (5.0 g, 28.4 mmol) and 2-fluoro-4- iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL), under N2 atmosphere was added lithium amide (2.61 g, 113.6 mmol) in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature and quenched with 1 N HCI and then water. The yellowish white precipitate was filtered, washed with water. The solid was triturated in CH2CI2 (30 mL) for 1h, filtered and dried in a vacuum oven at 45C for 14 hours to give 8.Og (72%) of compound (9) as an off-white solid, mp 201.5-203 C.General procedure: Benzoic acid, aniline, in a 5 mL microwave vialCharged with LiNH2 and THF.The vessel was microwaved at 200 C. for 3 minutes.Then, cool the reaction tube to room temperature, The mixture is treated with 1 M HCl aq.It was diluted with (20 mL) and extracted with CHCl 3 (20 mL × 3).The organic layers are combined, washed with brine and dried over anhydrous Na 2 SO 4, It concentrated under reduced pressure.Silica gel column chromatography of the residuePurification with (CHCl 3/10% AcOH-MeOH solution = 100/0 ' 90/10) gave the title compound. (A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (38; 2.38 g, 10.0 mmol), 2, 3, 4-trifluorobenzoic acid, (37; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 C and LiNH2 (561.2 mg, 24.45 mmol) was added in 3 portions over 10 min. The reaction was then warmed to an internal temperature of 58 C and stirred for 12 h. The mixture was cooled to 0 C and 1 N HC1 was added maintaining the reaction mixture at 0 C to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et20, washed three times with 5 mL portions of 1 N HC1, washed with NaCl (aq, sat), and dried over Na2S04. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on Si02 using 2: 1 hexane/EA to provide 2.11 g (53%) of a white solid. MP = 199.0 - 200.1 C (lit. MP = 200 - 201 C). Si02 TLC Rf 0.51 (2: 1 hexane/EA). 1H NMR (400 MHz, MeOD-d4): delta 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, = 1.8 Hz and J2 = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for Ci3H7F3IN02: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (26; 2.38 g, 10.0 mmol), 2, 3, 4-trifluorobenzoic acid, (25; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 oC and LiNH2 (561.2 mg, 24.45 mmol) was added in 3 portions over a 10 min interaval. The reaction was then warmed to an internal temperature of 58 oC and stirred for 12 h. The mixture was cooled to 0 oC and 1 N HCl was added maintaining the reaction mixture below 5 oC to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et2O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat), and dried over Na2SO4. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using 2:1 hexane/EA to provide 2.11 g (53%) of a white solid. MP = 199.0 - 200.1 oC (lit. MP = 200 - 201 oC). ADDIN EN.CITE Davis2005453454517Davis, Edward M.Nanninga, Thomas N.Tjiong, Howie I.Winkle, Derick D.Utilization of Lithium Amide in the Synthesis of N-Arylanthranilic Acids and N-ArylanthranilamidesOrg. Process Res. Dev.Org. Process Res. Dev.843-846920051083-6160&xD;1520-586Xhttp://pubs.acs.org/doi/pdfplus/10.1021/op0501242https://pubs.acs.org/doi/pdfplus/10.1021/op050124210.1021/op05012423 SiO2 TLC Rf 0.51 (2:1 hexane/EA). 1H NMR (400 MHz, MeOD-d4): delta 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, J1 = 1.8 Hz and J2 = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for C13H7F3INO2: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.EXAMPLE 6 1-F3, 4-DIFLUORO-2- (2-FLUORO-4-VINVIPHENYLAMINO)-PHENVLL-2-HYDROXV-ETHANONE Step A: Synthesis of R3, 4-DIFLUORO-2- (2-FLUORO-4-IODOD-PHENYLAMINO)-PHENVLL- methanol. To 3, 4-DIFLUORO-2-(2-FLUORO-4-IODO-PHENYLAMINO)-BENZOIC acid (10. 0g, 25. 4MMOL) in tetrahydrofuran was added, borane in tetrahydrofuran (38.2mL of a 1. OM solution) after 16 hours stirring at room temperature, the reaction was complete and quenched by careful addition of 2% HCI (100ML). The mixture was stirred for 1 H, brine was added and the organic layer was separated which was dried and evaporated to give a colorless solid (7. 13g 74%) that was recrystalized from hot dichloromethane/hexane to give an analytical sample. MS (APCI+) 380 (M+1+) ; H NMR (400mHz, DMSO) 7.62 (s, 1H), 7.50 (d, 1H), 7.24 (m, 3H), 6.29 (d of t, 1 H), 5.35 (t, 1 H), 4.42 (d, 1 H).Example 4. Preparation of N-((R)-2.3-dihydroxypropoxyV3.4-difluoro-2-(2-fluoro-4-iodo-phenylanriotainoV benzamide (Compound ) To a stirring solution of 3, 4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (120 g, 0.30 mol) in a mixture of 1 mL N, N-dimethylformamide and 1000 mL toluene was added thionyl chloride (55 g, 0.462 mol). The mixture was heated to 50-65 C and stirred for 2 hours or until reaction completion as determined by HPLC (Conditions E). The final reaction mixture was then cooled and concentrated under reduced pressure to a slurry keeping the temperature below 35C. Toluene (600 mL) was added to dissolve the slurry and vacuum distillation was repeated. Additional toluene (600 mL) was added to the slurry dissolving all solids and the solution was then cooled to 5 -10C. The solution was then treated with O-{[(4R)-2, 2-dimethyl-1, 3-dioxolan-4-yl]methyl}hydroxylamine (6) (63 g, 0.43 mol) solution in 207 mL toluene followed by potassium carbonate (65 g) and water (200 mL), stirred for at least 2 hours at 20- 25C. The stirring was stopped to allow phase separation and the bottom phase was discarded. The remaining organic layer was treated with hydrochloric acid solution (7.4%, 240 mL) until pH was less than 1 and stirred for 2 hours. The final reaction mixture was slightly concentrated under vacuum collecting about 100 mL distillate and the resulting organic solution was cooled to 5C to crystallize the product and filtered. The filter cake was washed with toluene (1000 mL) followed by water (100 mL) and the wet cake (crude product Compound I) was charged back to the flask. Toluene (100 mL), ethanol (100 mL) and water (100 mL) are then added, stirred at 30-35C for about 15 min, and the bottom aqueous phase was discarded. Water (200 mL) was then added to the organic solution and the mixture was stirred at about 3O C to allow for crystallization. The stirring was continued for 2 hours after product crystallized, then it was further cooled to about 0C and stirred for at least 2 hours. The slurry was filtered and wet cake was dried under reduced pressure at 55-85C to yield the final product N-((R)-2, 3-dihydroxypropoxy)-3, 4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I) product. Overall chemical yield was 86 g, 58%.1-3. 4-DIFLUORO-2- (2-FLUORO-4-IODO-PHENVLAMINO)-PHENVLL-2-HYDROXV-ETHANONE To a stirring suspension comprised of 3, 4-DIFLUORO-2- (2-FLUORO-4-IODO-PHENYLAMINO)- benzoic acid (1.33 g, 3.4 MMOL, which can be prepared according to the procedure of WO 02/06213) and oxalyl chloride (1.4 mL, 16 mmoles) in dichloromethane (10 mL) at ambient temperature was added 0.025 mL OF N, N-DIMETHYLFORMAMIDE. The reaction mixture was stirred for ten minutes and was concentrated in vacuo to the yellow solid 3, 4-DIFLUORO-2- (2- FLUORO-4-IODO-PHENYLAMINO)-BENZOYL chloride. The yellow solid was suspended in tris (trimethylsiloxy) ethylene (10 g, 33 MMOL) and the stirring mixture was brought to 90 C under a nitrogen atmosphere for six hours. The mixture was cooled slightly, and to it was added a solution consisting of dioxane (25 mL) and 10% aqueous hydrochloric acid (10 mL). Vigorous liberation of gas ensued and the mixture was stirred for ten minutes at 85 C. Brine (50 mL) was added and the mixture was extracted twice with ether (2 x 150 mL). The combined ether phases were washed twice with saturated aqueous sodium bicarbonate (2 x 150 mL). The ether phase was dried (MGS04) and was concentrated in vacuo to 1.4 g of an orange oil that was purified by flash chromatography. Elution with a gradient (100% hexanes to 1: 3 hexanes/ethyl acetate over 72 minutes) afforded a solid with minor impurities. The solid was dissolved in dichloromethane and vacuum filtered through silica to afford 0.135 g (9.8 % yield over two steps) of a yellow solid ; mp 128-128.5 C ; H-NMR (400 MHz; CDCl3) IB 9.80 (s, 1H), 7.40 (m, 3H), 6.77 (m, 2H), 4.83 (d, 2H, J=3.9 Hz), 3.44 (t, 1 H, J=4.1 Hz) ; 19F- NMR (376 MHz; CDCl3) 6-124. 52 (t, 1F, J=10.1 Hz), -125.27 (dd, 1F, J=10.1, 5.1 Hz), - 144.11 (d, 1F, J=7.7 Hz); MS (APCI+) 407.8 (M+1, 28), 389.8 (100); (APCI-) 405.8 (M-1, 100), 402.8 (53); IR 1662, 1529, 1503, 1260, 1067 CM~1 ; % C (calculated for C14H9F31NO2/FOUND) 41.30/41. 52, % H 2.23/2. 08, % N 3.44/3. 45.EXAMPLE 5 R3, 4-DIFLUORO-2-(2-FLUORO-4-IODO-PHENVLAM INO)-PHENYLL-(4-METHYL-OXAZOL-2-YL) methanone Step A: Synthesis of 314-DIFLUORO-2-(2-FLUORO-4-IODO-PHENVLAMINO)-BENZOYL CHLORIDE A solution of 3, 4-DIFLUORO-2-(2-FLUORO-4-IODO-PHENYLAMINO)-BENZOIC acid (5.0 g, 12.7 MMOL) in thionyl chloride (75 mL) containing 10 drops of dimethylformamide was heated at reflux for 15 min. The solvent was removed in vacuo affording 3, 4-DIFLUORO-2- (2-FLUORO-4-IODO- phenylamino)-benzoyl chloride (5.3 g, which can be prepared according to the procedure of WO 02/06213) as a yellow solidA dry 100 mL round bottomed flask was charged with 3, 4-difluoro-2-((2-fluoro-4- iodophenyl)amino)benzoic acid, (39) and 5 mL of DCM. The reaction mixture was cooled with an ice-bath to 0 C. 100 of anhydrous DMF was added followed by dropwise addition of neat oxalyl chloride (2 equiv.) over 5 min. The reaction was stirred at 23 C for 4 h. The solvent was then removed under reduced pressure. Excess oxalyl chloride was azeotropically removed with 2 X 5 mL portions of DCM under reduced pressure. The crude product was dissolved into 5 mL of DCM and the appropriate amine was added neat at 0 C. The ice bath was removed after 10 min and the reaction was permitted to warm to room temperature. The reaction was then stirred at 23 C for 6 h; completion of reaction was determined by TLC. A mixture of 10 mL of H20 and 10 mL of Et20 was added and the resultant mixture was extracted with Et20, washed with NaCl (aq, sat), and dried over Na2S04. The extract was decanted and then the solvent was removed under reduced pressure. The crude product was isolated on Si02 using hexane/EA.A dry 100 mL round bottomed flask was charged with a mixture of the substituted benzoic acid, and 5 mL of DCM. The reaction mixture was cooled with an ice-bath to 0 oC. A 100 muL volume of anhydrous DMF was added followed by dropwise addition of neat oxalyl chloride (2 equiv.) over 5 min. The reaction was stirred at 23 oC for 4 h. The solvent was removed under reduced pressure. Excess oxalyl chloride was azeotropically removed with 2 X 5 mL portions of DCM under reduced pressure. The crude acid chloride was dissolved into 5 mL of DCM and a greater than 2-fold stoichiometric ratio the appropriate amine was added neat at 0 oC. The ice bath was removed after 10 min and the reaction was permitted to warm to room temperature. The reaction was then stirred at 23 oC for 6 h; completion of reaction was determined by TLC. A mixture of 10 mL of H2O and 10 mL of Et2O was added and the resultant mixture was extracted with twice with 10 mL portions of Et2O, washed twice with 10 mL portions of NaCl (aq, sat), and dried over Na2SO4. The extract was decanted and then the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using hexane/EA.To a flask containing To a flask containing 3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzoic acid (2.6 Kg, 6.6 mol) and N, N'-carbonyldiimidazole (1.1 Kg, 6.8 mol) under nitrogen atmosphere, was added 12 L of dry acetonitrile. After stirring at 22 5C for about 90 minutes, a solution of (R)-O- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl)-hydroxylamine in toluene was added (8.5 L total volume, about 8 moles of amine). The solution was stirred for at least 6 hours at 22 5 C. Aqueous hydrochloric acid (9 L, 1.5 molar) was added, and after stirring for about 5 minutes, the layers were separated. Aqueous hydrochloric acid (9 L, 1.5 molar) was added to the remaining top layer, and after stirring for about 20 hours, the layers were separated. The remaining top layer was concentrated by vacuum distillation, and then diluted with 15 L toluene and 2 L ethanol. The mixture was warmed to 35-45C and diluted with 20 L warm water, then cooled to 0-5C. The product was collected by filtration and washed with 2 L toluene. The product was recrystallized by dissolving in 12 L toluene and 2 L ethanol (50 5 C), adding 10 L water and cooling to 0-5C. After collecting the product by filtration and washing with toluene, the product was dried in a vacuum oven resulting in 2.6 Kg of N-[(R)- 2, 3-Dihydroxypropoxy]-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide. 2.4 Kg of the above compound as a mixture of different crystalline forms was stirred in a mixture of 10 L water and 1 L ethanol at 35+ 5C for 20-30 hours, then cooled to 25+ 5C. The product was collected by filtration and washed with 1 L of water, then dried in a vacuum oven at 65C. This resulted in 2.3 Kg of material which was greater than 90% form IV. Note: DSC analysis shows an onset of melting at 110C with only a small amount of the peak with an onset of melting at 117C.Preparation 13 N-[(R)-2, 3-Dihydroxy-propoxy]-3, 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Form IV) To a flask containing To a solution of In an oven-dried three-neck, 2 L flask was taken 3, 4-DUFLUORO-2- [ (2- fluoro-4-iodophenyl) amino] benzoic acid (196.7g, 0.5 moles) and DMF (900 mL). To this stirred solution was added pyridine (44.4 mL, 43.5g, 0.55 moles) at RT, and then pentafluorophenyl trifluoroacetate (95 mL, 154g, 0.55 moles) was added dropwise within 30 minutes. The mixture was stirred at RT for 20 hours. The mixture was diluted with hexanes-diethyl ether (1 : 1, v/v, 3L) and washed successively with water (2x2L), 1M HC1 (2x2L), saturated NAHCO3 solution (2x2L) and finally with water (2x2L). The organic layer was dried and concentrated under reduced pressure to afford 2, 3, 4, 5, 6-pentafluorophenyl-3, 4- difluoro-2- [ (2-fluoro-4-iodophenyl) amino] benzoate as a red oil (92.3%, 258.5g).[0307] 2-(2-Fluoro-4-iodoanilino)-3, 4-difluorobenzoic acid (which can be prepared according to the procedure in PCT publication No. WO 00/41505) (5.00 g, 12.7 mmol) was dissolved in a mixture of Et2O (60 mL) and MeOH (30 mL), then TMS-diazomethane solution (8.27 ml of a 2 M solution in hexanes, 16.5 mmol) was added dropwise. This mixture was stirred at RT for 15 h., the excess reagent quenched with acetic acid, then all solvents removed under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL), which was washed with saturated NaHCO3 (2×200 mL), water (200 mL) and brine (100 mL). The EtOAc layer was then dried (Na2SO4) and the solvent removed under reduced pressure to afford methyl 3, 4-difluoro-2-(2-fluoro-4-iodoanilino)-3, 4-difluorobenzoate as a pink solid (5.16 g, 100%) which was used directly in the next step. 1H NMR [400 MHz, (CD3)2SO] delta 8.73 (s, 1H), 7.76 (ddd, J=9.0, 6.0, 2.1 Hz, 1H), 7.61 (dd, J=10.8, 1.9 Hz, 1H), 7.41 (ddd, J=8.5, 1.9, 1.0 Hz, 1H), 7.21-7.12 (m, 1H), 6.80 (ddd, J=8.8, 8.8, 4.4 Hz, 1H), 3.81 (s, 3H).

Intermediate in the preparation of MEK inhibitors.

Molecular Weight:393.10
XLogP3:4.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:392.94736
Monoisotopic Mass:392.94736
Topological Polar Surface Area:49.3
Heavy Atom Count:20
Complexity:361
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes