| 59% |
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 20℃; |
N-lodosuccinimide (3.31 g, 14.7 mmol) was added in portions over a 3-hour period to a stirred solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g, 14.7 mmol) in trifluoromethanesulphonic acid (15 mL) at 0 C. The mixture was warmed to room temperature, stirred overnight and then poured into an ice-water mixture and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried (MgSO4) and dried to give the title compound (3.45 g, 59%) as a solid. LRMS (m/z): 279 (M-1)-. 1H-NMR delta (CDCl3): 2.41 (s, 3H), 2.86 (m, 1H), 6.30 (brs, 1H), 7.72 (m, 1H), 8.34 (m, 1H). |
| 59% |
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; |
a) 3-Fluoro-5-iodo-4-methylbenzoic acid N-lodosuccinimide (3.31 g, 14.70 mmol) was added in portions over a 3-hour period to a stirred solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g, 14.70 mmol) in trifluoromethanesulphonic acid (15 mL) at 0 C. The mixture was warmed to room temperature, stirred overnight and then poured into an ice-water mixture and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried (MgSO4 and dried to give the title compound (3.45 g, 59%) as a solid. LRMS (m/z): 279 (M-1)-.1H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.41 (s, 3 H), 2.86 (m, 1 H), 6.30 (br. s , 1 H), 7.72 (m, 1 H), 8.34 (m, 1 H) |
| 59% |
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃;Product distribution / selectivity; |
INTERMEDIATE 9; 3-(3-Fluoro-5-iodo-4-methylpheny -5-methyl-4 -1,2,4-triazole; a) 3-Fluoro-5-iodo-4-methylbenzoic acid; /V-lodosuccinimide (3.31 g, 14.70 mmol) was added in portions over a 3-hour period to a stirred solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g, 14.70 mmol) in trifluoromethanesulphonic acid (15 mL) at 0 C. The mixture was warmed to room temperature, stirred overnight and then poured into an ice-water mixture and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried (MgS04) and dried to give the title compound (3.45 g, 59%) as a solid.LRMS (m/z): 279 (M-1)".1 H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.41 (s, 3 H), 2.86 (m, 1 H), 6.30 (br. s , 1 H), 7.72 (m, 1 H), 8.34 (m, 1 H) |
| 53% |
|
10c) 3-fluoro-5-iodo-4-methylbenzoic acid3-Fluoro-4-methyl benzoic acid (120 g, 0.78 mol) was added to triflic acid (830 mL) at O0C and the resultant mixture was cooled to -150C. N- lodosuccinimide (157 g, 0.70mol) was then added in five portions over 30 min, EPO <DP n="66"/>while the temperature of the reaction mixture was kept below -100C, and the resultant mixture was stirred at 00C for 3 h. A further portion of Lambda/-iodosuccinimide (58 g, 0.20mol) was added and after being left to stand in the fridge for 24 h, a final portion (35 g, 0.16 mol) was added, and the reaction was left to stand in the fridge for a further 3 days. The reaction mixture was then poured into a mixture of ice (2.3 kg) and 10% aqueous sodium thiosulphate (1.2 L) and allowed to warm to room temperature. The resultant solid was collected by filtration, washed with water, air-dried, and taken up in ethyl acetate (4.0 L). The organic solution was then washed with 10% aqueous sodium thiosulphate (2 x 1.0 L) and saturated aqueous sodium chloride, and the aqueous phase was further extracted with ethyl acetate (2 x 1.0 L). The combined organic fractions were then dried (MgSO4) and concentrated to a volume of about 320 mL, and the resultant solid was collected by filtration, washed with hexane, and air-dried to afford 3-fluoro-5- iodo-4-methylbenzoic acid (116 g, 53%) as an off-white solid. 26a) 3-fluoro-5-iodo-4-methylbenzoic acid3-Fluoro-4-methyl benzoic acid (120 g, 0.78 mol) was added to triflic acid (830 mL) at 00C and the resultant mixture was cooled to -150C. N- lodosuccinimide (157 g, 0.70mol) was then added in five portions over 30 min, while the temperature of the reaction mixture was kept below -100C, and the resultant mixture was stirred at O0C for 3 h. A further portion of N- iodosuccinimide (58 g, 0.20mol) was added and after being left to stand in the fridge for 24 h, a final portion (35 g, 0.16 mol) was added, and the reaction EPO <DP n="78"/>was left to stand in the fridge for a further 3 days. The reaction mixture was then poured into a mixture of ice (2.3 kg) and 10% aqueous sodium thiosulphate (1.2 L) and allowed to warm to room temperature. The resultant solid was collected by filtration, washed with water, air-dried, and taken up in ethyl acetate (4.0 L). The organic solution was then washed with 10% aqueous sodium thiosulphate (2 x 1.0 L) and saturated aqueous sodium chloride, and the aqueous phase was further extracted with ethyl acetate (2 x 1.0 L). The combined organic fractions were then dried (MgSO4) and concentrated to a volume of about 320 mL, and the resultant solid was collected by filtration, washed with hexane, and air-dried to afford the title compound (116 g, 53%) as an off-white solid. |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -20 - -10℃; for 64.67h; |
A stirred mixture of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (10.3g) in trifluoromethane sulfonic acid (50ml) at -20C was treated with N-iodosuccinimide in portions over 40min. The reaction was stirred at -10C for 44h when a further amount of N-iodosuccinimide (6.0g) was added. After 20h the reaction mixture was added to ice/water and extracted with ethyl acetate. The organic solution was washed with aqueous sodium metabisulfite and dried over sodium sulfate. The residue was dissolved in methanol (50ml), the solution was treated with concentrated sulfuric acid (91ml) and the mixture was heated at reflux for 6h. The solvent was evaporated and the residue was dissolved in ethyl acetate. This solution was washed with aqueous sodium bicarbonate and dried with brine and over magnesium sulfate. Purification by biotage chromatography (x2), firstly using cyclohexane/ethyl acetate (100/1) and secondly cyclohexane/toluene (6/1) as eluents gave the title compound (9.31 g). LC-MS: Rt 3.55min. |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -20℃; for 48.25h; |
A solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (149.7g) in trifluoromethanesulphonic acid (1050ml) at -22C under nitrogen was treated portionwise over 1.25h with iodosuccinimide (203.5g). The mixture was stirred at -20C for and further portions of iodosuccinimide were added after 2.5h (46.5g) and 20.5h (30g). The mixture was stirred at -20C for a further 24h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5L) and ice (3kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5L) and aqueous sodium thiosulphate (10%, 1.5L). The organic phase was dried (MgSO4) and concentrated to -1.5L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133.9g). LC-MS: Rt 3.60, MH+ 281. |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; |
Example 49; iV-cyclopropyl-3-(8-(2,6-difluorophenyl)-2-[2-hydroxy-l-(hydroxymethv?ethyl1amino|-7-oxo-7,8-dihydropyrido["2.3-cr|pyrimidin-4-ylV5- fluoro-4-rnethylbenzamide EPO <DP n="78"/>3-Fluoro-4-methylbenzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoromethanesulfonic acid (10 mL) and cooled to about 0 0C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 00C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3x). The organic layers are washed (Na2S2O5) and concentrated. The material is carried on crude.The crude acid from above (~1.5 g) is dissolved in thionyl chloride (75 mL) and heated to 80 0C for about 2 h. The mixture is then cooled to room temperature and stirred under N2 overnight. The mixture is concentrated in vacuo and dissolved in 15 mL DCM. Na2CO3 (3g) is added along with the cyclopropyl amine (0.69 mL, 0.01 moles (hereinafter "mol")). The mixture is allowed to stir overnight and purified via flash chromatography (5% MeOH / CH2Cl2) to afford 0.904g of N-cyclopropyl-3- fluoro-5-iodo-4-methylbenzamide iV-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide (0.904 g, 2.83 mmol) is dissolved in DMF (30 mL). Bis-pinicalato-diborane (1.44 g, 2.83 mmol) is added followed by PdCl2. dppf (55 mg) and potassium acetate (1.38 g, 14.15 mmol). The mixture are stirred for about 18 h, concentrated in vacuo and purified via flash chromatography to afford N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzamide (60 mg).4-Chloro-8-(2,6-difluorophenyl)-2-[2-hydroxy-l-(hydroxymethyl)ethyl]- amino}pyrido[253-<^pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), N-cyclopropyl-3- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05eq) are dissolved in dioxane / water (3:1, 10 mL) and heated to about 100 0C for about 3 h. The mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure. |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -18℃;Product distribution / selectivity; |
3-Fluoro-4-methylbenzoic acid (182g) was added to trifluoromethanesulphonic acid (1.121) and the solution cooled to -200C under nitrogen, lodosuccinimide (266g) was added in portions over 75min, maintaining a reaction temperature of -18 to -19C, and the reaction was then stirred at -200C for 4hours. lodosuccinimide (54.8g) was added portionwise and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at - 200C for a further 24hours. The reaction was warmed to -5C and the suspension poured into a stirred mixture of ice (3kg) and sodium thiosulphate solution (10%). The mixture was filtered and the solid partially dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51), the organic washed with sodium thiosulphate solution (10%) and dried (sodium sulphate), before concentrating in vacuo to ca. 600ml. The resulting slurry was allowed to stand for 4hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (215g). LCMS: [M-H]" 279, retention time 3.75min.; 3-Fluoro-4-methylbenzoic acid (150.3g) was added to trifluoromethanesulphonic acid (1.051) and the solution cooled to -22C under nitrogen, lodosuccinimide (200.8g) was added in portions over 60min, maintaining a reaction temperature of -19 to -22C, and the reaction was then stirred at -200C for 2.5hours. lodosuccinimide (51.0) was added portionwise over 30min and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at -200C for a further 17hours. A further portion of iodosuccinimide (28.2g) and stirring continued at -200C for a further 24hours. The reaction was poured into a stirred mixture of ice (3kg) and 10% sodium thiosulphate solution (1.5L). The mixture was filtered, washed with water and the solid dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51). The organic layer was washed with sodium thiosulphate solution (10%, 1.51) and the aqueous phases back extracted with ethyl acetate. The organic phases were combined and drwashed with brine and dried (magnesium sulphate), before concentrating in vacuo to approximately 750ml. The resulting mixture was allowed to stand for 24hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (126.5g). LCMS: [M-H]" 279, retention time 3.6min. |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -5℃;Product distribution / selectivity; |
Intermediate 1 : 3-Fluoro-5-iodo-4-methylbenzoic acid - preparation 1; 3-Fluoro-4-methylbenzoic acid (182g) was added to trifluoromethanesulphonic acid (1.121) and the solution cooled to -200C under nitrogen, lodosuccinimide (266g) was added in portions over 75min, maintaining a reaction temperature of -18 to -19C, and the reaction was then stirred at -200C for 4hours. lodosuccinimide (54.8g) was added portionwise and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at - 200C for a further 24hours. The reaction was warmed to -5C and the suspension poured into a stirred mixture of ice (3kg) and sodium thiosulphate solution (10%). The mixture was filtered and the solid partially dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51), the organic washed with sodium thiosulphate solution (10%) and dried (sodium sulphate), before concentrating in vacuo to ca. 600ml. The resulting slurry was allowed to stand for 4hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (215g). LCMS: [M-H]" 279, retention time 3.75min.; Intermediate 1 : 3-Fluoro-5-iodo-4-methylbenzoic acid - preparation 2; 3-Fluoro-4-methylbenzoic acid (150.3g) was added to trifluoromethanesulphonic acid (1.051) and the solution cooled to -22C under nitrogen, lodosuccinimide (200.8g) was added in portions over 60min, maintaining a reaction temperature of -19 to -22C, and the reaction was then stirred at -200C for 2.5hours. lodosuccinimide (51.0) was added portionwise over 30min and the reaction stirred at -200C overnight, lodosuccinimide (19g) added before stirring at -200C for a further 17hours. A further portion of iodosuccinimide <n="21"/>(28.2g) and stirring continued at -200C for a further 24hours. The reaction was poured into a stirred mixture of ice (3kg) and 10% sodium thiosulphate solution (1.5L). The mixture was filtered, washed with water and the solid dried on the sinter. The solid was partitioned between ethyl acetate (5I) and sodium thiosulphate solution (10%, 1.51). The organic layer was washed with sodium thiosulphate solution (10%, 1.51) and the aqueous phases back extracted with ethyl acetate. The organic phases were combined and drwashed with brine and dried (magnesium sulphate), before concentrating in vacuo to approximately 750ml. The resulting mixture was allowed to stand for 24hours, filtered, the residue washed with ethyl acetate and dried, to give 3-fluoro-5-iodo-4-methylbenzoic acid (126.5g). LCMS: [M-H]" 279, retention time 3.6min. |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; |
N-Iodosuccinimide (22. 5g) was added in portions to a solution of 3-fluoro-4- methylbenzoic acid (15.4g) in trifluoromethanesulphonic acid (100ml) at 0C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ml) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl chloride (30ml) and heated at 100C for 2. 5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ml). Sodium carbonate (25g) and cyclopropylamine (13ml) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate/cyclohexane gradient (22-28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N- cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide. LCMS; MH+ 320, retention time 3. 16minutes. |
|
With N-iodo-succinimide; trifluoroacetic acid; at 0 - 20℃; |
Intermediate 7: N-CVCLOPROPVL-5-FLUORO-3-IODO-4-METHVLBENZAMIDE; N-LODOSUCCINIMIDE (22.5g) was added in portions to a solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (15. 4g) in TRIFLUOROMETHANESULPHONIC acid (100MOL) at 0C over 3hours and the reaction then allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water (400ML) and the precipitate filtered off and washed with water. The solid remaining was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was mixed with thionyl CHLORIDE (30M1) and heated at 100C for 2.5hours. The excess thionyl chloride was removed from the cooled reaction under vacuum and the residue dissolved in DCM (100ML). Sodium carbonate (25g) and CYCLOPROPYLAMINE (13ML) were added to the solution and the reaction stirred at room temperature for 72hours. The reaction was filtered and the residue washed with DCM and ethyl acetate. The solvent was evaporated from the combined filtrate and washings under vacuum. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate/cyclohexane gradient (22-28% ethyl acetate). Appropriate fractions were reduced to dryness under vacuum to give N-cyclopropyl-5-fluoro-3-iodo-4- methylbenzamide. LCMS; MH+ 320, retention time 3.16minutes |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -20℃; for 48.25h; |
Intermediate 11 : 3-Fluoro-5-iodo-4-methylbenzoic acid; A solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (149.7g) in trifluoromethanesulphonic acid (1050m1) at-22C under nitrogen was treated portionwise over 1.25h with iodosuccinimide (203.5g). The mixture was stirred at-20C for and further portions of iodosuccinimide were added after 2.5h (46.5g) and 20.5h (30g). The mixture was stirred at-20C for a further 24h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5L) and ice (3kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5L) and aqueous sodium thiosulphate (10%, 1.5L). The organic phase was dried (MgS04) and concentrated to-1.5L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133. 9g). LC-MS: Rt 3. 60, MH+ 281 |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at -22 - -20℃; for 48.25h; |
Intermediate 29: 3-Fluoro-5-iodo-4-methvlbenzoic acid; A solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (149.7g) in trifluoromethanesulphonic acid (1050ml) at-22C under nitrogen was treated portionwise over 1.25h with iodosuccinimide (203.5g). The mixture was stirred at-20C for and further portions of iodosuccinimide were added after 2.5h (46.5g) and 20.5h (30g). The mixture was stirred at-20C for a further 24h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5L) and ice (3kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5L) and aqueous sodium thiosulphate (10%, 1.5L). The organic phase was dried (MgS04) and concentrated to-1.5L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133. 9g). LC-MS : Rt 3. 60, MH+ 281 |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; |
Example 18; N-cyclopropyl-3-f 8-(2,6-difluorophenyl)-2- (["2-hvdroxy-l -QivdroxLambdamiethyl)ethyl1amino}-7-oxo-7,8-dihvdropyridor2.l3--(f|pyrimidin-4-y?-5- fluoro-4-methylbenzarnideThe benzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoroniethanesulfonic acid (10 mL) and cooled to about 00C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 0 0C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3x). The organic layers are washed (Na2SaO5) and concentrated. The material is carried on crude. |
|
With N-iodo-succinimide; In trifluorormethanesulfonic acid; at 0 - 20℃; |
3-Fluoro-4-methylbenzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoromethanesulfonic acid (10 mL) and cooled to about 0 0C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 0 0C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3x). The organic layers are washed (Na2S2Os) and concentrated. The material is carried on crude.The crude acid from above (~1.5 g) is dissolved in thionyl chloride (75 mL) and heated to 80 0C for about 2 h. The mixture is then cooled to room temperature and stirred under N2 overnight. The mixture is concentrated in vacuo and dissolved in 15 mL DCM. Na2CO3 (3g) is added along with the cyclopropyl amine (0.69 mL, 0.01 moles (hereinafter "mol")). The mixture is allowed to stir overnight and purified via flash chromatography (5% MeOH / CH2Cl2) to afford 0.904g of N-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamidelambda/-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide (0.904 g, 2.83 mmol) is dissolved in DMF (30 mL). Bis-pinicalato-diborane (1.44 g, 2.83 mmol) is added followed by PdCl2. dppf (55 mg) and potassium acetate (1.38 g, 14.15 mmol). The mixture are stirred for about 18 h, concentrated in vacuo and purified via flash chromatography to afford N- cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (60 mg).4-Chloro-8-(2,6-difluorophenyl)-2-[2-hydroxy-l-(hydroxymethyl)ethyl]- amino}pyrido[2,3-(i]pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), iV-cyclopropyl-3-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05eq) are dissolved in dioxane / water (3:1, 10 mL) and heated to about 100 0C for about 3 h. The <n="76"/>mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure. |
|
With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0℃; |
lambda/-lodosuccinimide (3.31 g) was added in portions to a solution of <strong>[350-28-7]3-fluoro-4-methylbenzoic acid</strong> (2.27 g) in trifluoromethanesulphonic acid (15 mL) at 0c over 3 hours and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into ice/water and the precipitate was collected by filtration and rinsed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulphate and brine, dried over anhydrous magnesium sulphate and the solvent was removed under vacuum. The residue obtained was treated with thionyl chloride (20 mL) and heated at 1000C for 2.5 hours. Excess thionyl chloride was removed under vacuum and the residue was dissolved in dichloromethane (20 mL). Sodium carbonate (3.7 g) and cyclopropylamine (1.9 mL) were added to the solution and the mixture was stirred at room temperature for 72 hours. The mixture was filtered and the residue was rinsed with dichloromethane and ethyl acetate. The combined filtrates and washings were concentrated under vacuum.The residue was purified by flash chromatography eluting with hexanes:ethyl acetate (10:1 to 5:1) to give 2.13 g (45%) of lambda/-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide. |
|
With N-iodo-succinimide; methanesulfonic acid; at -20 - -18℃;Product distribution / selectivity; |
Intermediate 1: 3-Fluoro-5-iodo-4-methylbenzoic acid; 3-Fluoro-4-methylbenzoic acid (182g) was added to trifluoromethanesulphonic acid (1.12L) and the solution cooled to -200C under nitrogen, lodosuccinimide (266g) was added in portions over 75min, maintaining a reaction temperature of -18 to -19C, and the reaction was then stirred at -200C for 4h. lodosuccinimide (54.8g) was added portionwise and the reaction stirred at -2O0C overnight, lodosuccinimide (19g) added before stirring at -200C for a further 24h. The reaction was warmed to -5C and the suspension poured into a stirred mixture of ice (3kg) and sodium thiosulphate solution (10%). The mixture was filtered and the solid partially dried on the sinter. The solid was partitioned between ethyl acetate (5L) and aqueous sodium thiosulphate solution (10%, 1.5L) and the organic phase was washed with sodium thiosulphate solution (10%) dried (sodium sulphate) and concentrated under vacuum to ca. 600ml. The resulting slurry was allowed to stand for 4h and the solid was collected by filtration, washed with ethyl acetate and dried, to give the title compound (215g). LC-MS: Rt 3.75min. |
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