3-(methylsulfonylmethyl)aniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[3-(Methylsulfonylmethyl)phenyl]N-methylamine may be obtained by carrying out the procedure in the following manner: a mixture of 9.65 cm3 of formic acid and 19.63 cm3 of acetic anhydride is heated at 50° C. for 3 hours under argon, and then the solution obtained is allowed to return to room temperature. 40 cm3 of tetrahydrofuran are poured in and the medium is cooled to −20° C. After stirring for 2 hours at −20° C., a solution of 14.8 g of 3-(methylsulfonylmethyl)phenylamine is poured in while the temperature is maintained. After stirring for 2 hours at −20° C., and then for 48 hours at 20° C., the mixture is filtered, the solid is drained and then washed with three times 50 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa). A solid A is obtained. The filtrate is concentrated to half the volume, the resulting suspension is filtered, the solid is drained, washed with diisopropyl ether and dried. A solid B is obtained. The two solids A and B are combined and taken up in 375 cm3 of tetrahydrofuran and the mixture, cooled to 0° C., is supplemented, over 20 minutes, with 80 cm3 of a 2 M solution of borane-dimethyl sulfide complex in tetrahydrofuran and then heated at reflux temperature for 3 hours. The reaction mixture, cooled to +5° C., is supplemented over 20 minutes with 60 cm3 of methanol, stirred for 1 hour at room temperature and then supplemented with gaseous hydrochloric acid to a pH of 1. The mixture is heated under reflux for one hour and then supplemented with 300 cm3 of water and with a 3 N solution of sodium hydroxide to pH 8. The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution, and with brine, and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of 4 N sulfuric acid, the solution obtained is washed with 100 cm3 of ethyl acetate, then alkalinized to pH 8 with 3 N sodium hydroxide and with a saturated aqueous sodium carbonate solution and is then extracted with twice 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of N-[3-(methylsulfonylmethyl)phenyl]N-methylamine are obtained in the form of a pink solid. the solution obtained to return to room temperature is cooled to −20° C is maintained After stirring for 2 hours at −20° C. for 48 hours at 20° C. the mixture is filtered washed with three times 50 cm3 of diisopropyl ether dried under reduced pressure (2.7 kPa) A solid A is obtained The filtrate is concentrated to half the volume the resulting suspension is filtered washed with diisopropyl ether dried A solid B is obtained the mixture, cooled to 0° C. heated at reflux temperature for 3 hours The reaction mixture, cooled to +5° C. stirred for 1 hour at room temperature The mixture is heated under reflux for one hour The resulting mixture is extracted with 500 cm3 of ethyl acetate the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution with brine, and is then dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa) the solution obtained is washed with 100 cm3 of ethyl acetate is then extracted with twice 75 cm3 of ethyl acetate The combined extracts are dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[3-(Methylsulfonylmethyl)phenyl]N-methylamine may be obtained by carrying out the procedure in the following manner: a mixture of 9.65 cm3 of formic acid and 19.63 cm3 of acetic anhydride is heated at 50° C. for 3 hours under argon, and then the solution obtained is allowed to return to room temperature. 40 cm3 of tetrahydrofuran are poured in and the medium is cooled to −20° C. After stirring for 2 hours at −20° C., a solution of 14.8 g of 3-(methylsulfonylmethyl)phenylamine is poured in while the temperature is maintained. After stirring for 2 hours at −20° C., and then for 48 hours at 20° C., the mixture is filtered, the solid is drained and then washed with three times 50 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa). A solid A is obtained. The filtrate is concentrated to half the volume, the resulting suspension is filtered, the solid is drained, washed with diisopropyl ether and dried. A solid B is obtained. The two solids A and B are combined and taken up in 375 cm3 of tetrahydrofuran and the mixture, cooled to 0° C., is supplemented, over 20 minutes, with 80 cm3 of a 2 M solution of borane-dimethyl sulfide complex in tetrahydrofuran and then heated at reflux temperature for 3 hours. The reaction mixture, cooled to +5° C., is supplemented over 20 minutes with 60 cm3 of methanol, stirred for 1 hour at room temperature and then supplemented with gaseous hydrochloric acid to a pH of 1. The mixture is heated under reflux for one hour and then supplemented with 300 cm3 of water and with a 3 N solution of sodium hydroxide to pH 8. The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution, and with brine, and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of 4 N sulfuric acid, the solution obtained is washed with 100 cm3 of ethyl acetate, then alkalinized to pH 8 with 3 N sodium hydroxide and with a saturated aqueous sodium carbonate solution and is then extracted with twice 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of N-[3-(methylsulfonylmethyl)phenyl]N-methylamine are obtained in the form of a pink solid. the solution obtained to return to room temperature is cooled to −20° C is maintained After stirring for 2 hours at −20° C. for 48 hours at 20° C. the mixture is filtered washed with three times 50 cm3 of diisopropyl ether dried under reduced pressure (2.7 kPa) A solid A is obtained The filtrate is concentrated to half the volume the resulting suspension is filtered washed with diisopropyl ether dried A solid B is obtained the mixture, cooled to 0° C. heated at reflux temperature for 3 hours The reaction mixture, cooled to +5° C. stirred for 1 hour at room temperature The mixture is heated under reflux for one hour The resulting mixture is extracted with 500 cm3 of ethyl acetate the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution with brine, and is then dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa) the solution obtained is washed with 100 cm3 of ethyl acetate is then extracted with twice 75 cm3 of ethyl acetate The combined extracts are dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dry flask containing a magnetic stir bar and a nitrogen atmosphere was added 0.247 g (1.33 mmol) of 3-[(methylsulfonyl)methyl]aniline, 2 mL dry acetonitrile and 0.23 mL (1.3 mmol) of diisopropylethyl amine and resultant mixture cooled in an ice bath. To the cold solution was added a solution of 0.2 g (1.33 mmol) of 2,4-dichloro-1,3,5-triazine in 2.4 mL of dry acetonitrile over 1 min. The reaction mixture was stirred for ca. 16 hrs and 1 gram of silica gel was added. The mixture was concentrated in vacuo to dryness and applied to the top of column of silica gel and eluted with a 15-50% ethyl acetate/dichloromethane gradient. The proper fractions were combined and concentrated in vacuo to give 0.28 g (70%) of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine as a white solid. HNMR: δ 10.83 (s, 1H), 8.64 (s, 1H), 7.63 (m, 2H), 7.4 (t, 1H), 7.25 (d, 1H), 4.48 (s, 2H), 2.94 (s, 3H); MS (ES+, m/z) 299, 301 (M+H). To a dry flask containing a magnetic stir bar cooled in an ice bath 1 gram of silica gel was added The mixture was concentrated in vacuo to dryness eluted with a 15-50% ethyl acetate/dichloromethane gradient concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 16.2 was prepared under similar conditions as described in the preparation of Example 3. using 2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (Intermediate 16.1) and 3-[(methylsulfonyl)methyl]aniline (Intermediate 1.3). The batch was purified by preparative HPLC. Example 16.2 was prepared under similar conditions as described in the preparation of Example 3 The batch was purified by preparative HPLC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(III)chloride solution (about 15%) in about 10% hydrochloric acid (162 mL; Merck Schuchardt OHG) was added to a stirred solution of 1-[(methylsulfonyl)methyl]-3-nitrobenzene (5.1 g; 23.8 mmol) in THF (250 mL) at room temperature and the batch was stirred for 16 hours. By adding 1N sodium hydroxide solution the pH value of the reaction mixture was raised to 10 before the batch was extracted with ethyl acetate (2×). The combined organic phases were washed with brine, filtered using a Whatman filter and concentrated to give the desired product (4.5 g) that was used without further purification. was raised to 10 before the batch was extracted with ethyl acetate (2×) The combined organic phases were washed with brine filtered filter concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[3-(Methylsulfonylmethyl)phenyl]N-methylamine may be obtained by carrying out the procedure in the following manner: a mixture of 9.65 cm3 of formic acid and 19.63 cm3 of acetic anhydride is heated at 50° C. for 3 hours under argon, and then the solution obtained is allowed to return to room temperature. 40 cm3 of tetrahydrofuran are poured in and the medium is cooled to −20° C. After stirring for 2 hours at −20° C., a solution of 14.8 g of 3-(methylsulfonylmethyl)phenylamine is poured in while the temperature is maintained. After stirring for 2 hours at −20° C., and then for 48 hours at 20° C., the mixture is filtered, the solid is drained and then washed with three times 50 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa). A solid A is obtained. The filtrate is concentrated to half the volume, the resulting suspension is filtered, the solid is drained, washed with diisopropyl ether and dried. A solid B is obtained. The two solids A and B are combined and taken up in 375 cm3 of tetrahydrofuran and the mixture, cooled to 0° C., is supplemented, over 20 minutes, with 80 cm3 of a 2 M solution of borane-dimethyl sulfide complex in tetrahydrofuran and then heated at reflux temperature for 3 hours. The reaction mixture, cooled to +5° C., is supplemented over 20 minutes with 60 cm3 of methanol, stirred for 1 hour at room temperature and then supplemented with gaseous hydrochloric acid to a pH of 1. The mixture is heated under reflux for one hour and then supplemented with 300 cm3 of water and with a 3 N solution of sodium hydroxide to pH 8. The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution, and with brine, and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of 4 N sulfuric acid, the solution obtained is washed with 100 cm3 of ethyl acetate, then alkalinized to pH 8 with 3 N sodium hydroxide and with a saturated aqueous sodium carbonate solution and is then extracted with twice 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of N-[3-(methylsulfonylmethyl)phenyl]N-methylamine are obtained in the form of a pink solid. the solution obtained to return to room temperature is cooled to −20° C is maintained After stirring for 2 hours at −20° C. for 48 hours at 20° C. the mixture is filtered washed with three times 50 cm3 of diisopropyl ether dried under reduced pressure (2.7 kPa) A solid A is obtained The filtrate is concentrated to half the volume the resulting suspension is filtered washed with diisopropyl ether dried A solid B is obtained the mixture, cooled to 0° C. heated at reflux temperature for 3 hours The reaction mixture, cooled to +5° C. stirred for 1 hour at room temperature The mixture is heated under reflux for one hour The resulting mixture is extracted with 500 cm3 of ethyl acetate the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution with brine, and is then dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa) the solution obtained is washed with 100 cm3 of ethyl acetate is then extracted with twice 75 cm3 of ethyl acetate The combined extracts are dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[3-(Methylsulfonylmethyl)phenyl]N-methylamine may be obtained by carrying out the procedure in the following manner: a mixture of 9.65 cm3 of formic acid and 19.63 cm3 of acetic anhydride is heated at 50° C. for 3 hours under argon, and then the solution obtained is allowed to return to room temperature. 40 cm3 of tetrahydrofuran are poured in and the medium is cooled to −20° C. After stirring for 2 hours at −20° C., a solution of 14.8 g of 3-(methylsulfonylmethyl)phenylamine is poured in while the temperature is maintained. After stirring for 2 hours at −20° C., and then for 48 hours at 20° C., the mixture is filtered, the solid is drained and then washed with three times 50 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa). A solid A is obtained. The filtrate is concentrated to half the volume, the resulting suspension is filtered, the solid is drained, washed with diisopropyl ether and dried. A solid B is obtained. The two solids A and B are combined and taken up in 375 cm3 of tetrahydrofuran and the mixture, cooled to 0° C., is supplemented, over 20 minutes, with 80 cm3 of a 2 M solution of borane-dimethyl sulfide complex in tetrahydrofuran and then heated at reflux temperature for 3 hours. The reaction mixture, cooled to +5° C., is supplemented over 20 minutes with 60 cm3 of methanol, stirred for 1 hour at room temperature and then supplemented with gaseous hydrochloric acid to a pH of 1. The mixture is heated under reflux for one hour and then supplemented with 300 cm3 of water and with a 3 N solution of sodium hydroxide to pH 8. The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution, and with brine, and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of 4 N sulfuric acid, the solution obtained is washed with 100 cm3 of ethyl acetate, then alkalinized to pH 8 with 3 N sodium hydroxide and with a saturated aqueous sodium carbonate solution and is then extracted with twice 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of N-[3-(methylsulfonylmethyl)phenyl]N-methylamine are obtained in the form of a pink solid. the solution obtained to return to room temperature is cooled to −20° C is maintained After stirring for 2 hours at −20° C. for 48 hours at 20° C. the mixture is filtered washed with three times 50 cm3 of diisopropyl ether dried under reduced pressure (2.7 kPa) A solid A is obtained The filtrate is concentrated to half the volume the resulting suspension is filtered washed with diisopropyl ether dried A solid B is obtained the mixture, cooled to 0° C. heated at reflux temperature for 3 hours The reaction mixture, cooled to +5° C. stirred for 1 hour at room temperature The mixture is heated under reflux for one hour The resulting mixture is extracted with 500 cm3 of ethyl acetate the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution with brine, and is then dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa) the solution obtained is washed with 100 cm3 of ethyl acetate is then extracted with twice 75 cm3 of ethyl acetate The combined extracts are dried over magnesium sulfate concentrated to dryness under reduced pressure (2.7 kPa)

Conditions: temp:100.01; pressure:0.00; stir:

Procedure: 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (0.25 g, 0.97 mmol), 3-((methylsulfonyl)methyl)aniline (0.180 g, 0.97 mmol), cesium carbonate (1.270 g, 3.90 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.141 g, 0.24 mmol)and Pd2(dba)3 (0.178 g, 0.19 mmol) were suspended in degassed 1,4-dioxane (3 mL) at ambient temperature. The resulting mixture was degassed, purged with nitrogen and heated at 100 °C for 3 hours after which time reaction was shown to be complete by LC-MS. The mixture was allowed to cool overnight. The reaction mixture was diluted with water (250 mL), and extracted with DCM (250 mL). The organic was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in Heptane. Fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5µ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-(3-((methylsulfonyl)methyl)phenyl)pyrimidin-2-amine (0.200 g, 50.6 %) as a white solid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 3-(methylsulfonylmethyl)aniline and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave N4-cyclobutyl-N2-(3-methylsulfonylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine (MS calcd for C18H21N5O2S 371.5, found [MH] 372.1; UV 214.5, 267.6, 304.5 nm).

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1-(methylsulfonylmethyl)-4-nitrobenzene (0.77 g, 3.56 mmol) in EtOH (10 mL) and H2O (5 mL) was added iron (1.0 g, 17.82 mmol) and ammonium formate (2.25 g, 35.6 mmol). After heating at 90° C. for 2 h, it was diluted with EtOAc, washed with saturated NaHCO3, brine, dried and concentrated to give 3-(methylsulfonylmethyl)aniline (0.47 g). washed with saturated NaHCO3, brine dried concentrated