2-methyl-3-methylsulfanylpropanoyl chloride

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet was charged 7.5 g (30.2 mmoles) of 4-chloro-2-(pyridine-3-yl)-1,3-thiazol-5-amine hydrochloride and 200 mLs of anhydrous methylene chloride. The resulting suspension was cooled to 15° C., and 5.98 g (76 mmoles) of pyridine was added at a rate that maintained the temperature below 20° C. 1.85 g (15.11 mmoles) of N,N-dimethylpyridin-4-amine was added in one portion and the resulting yellow solution was stirred at 5° C. for 10 minutes. A solution of 2-methyl-3-(methylthio)propanoyl chloride (5.54 g 36.3 mmoles) in 25 mLs of methylene chloride was added dropwise at a rate that maintained the temperature below 15° C. The reaction was stirred at ambient temperature for 12 hours, than poured into 200 mLs of water. The target was extracted with methylene chloride (3×100 mLs) and the combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes to yield a yellow oil (5.4 g, 55%): 1H NMR (400 MHz, CDCl3) δ 9.12 (dd, J=2.3, 0.8 Hz, 1H), 9.00 (s, 1H), 8.64 (dd, J=4.8, 1.6 Hz, 1H), 8.17 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 7.37 (ddd, J=8.0, 4.9, 0.8 Hz, 1H), 3.00-2.57 (m, 3H), 2.17 (s, 3H), 1.38 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.68, 155.24, 150.55, 146.75, 132.81, 129.26, 127.62, 124.99, 123.80, 40.85, 37.98, 17.46, 16.45. To a dry 500 ml round bottom flask equipped with magnetic stirrer thermometer, addition funnel, and nitrogen inlet maintained the temperature below 20° C that maintained the temperature below 15° C The reaction was stirred at ambient temperature for 12 hours The target was extracted with methylene chloride (3×100 mLs) the combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs) The organic extract was dried over anhydrous magnesium sulfate filtered concentrated under vacuum on a rotary evaporator The crude product was purified by silica gel flash chromatography eluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet was charged 7.5 g (30.2 mmoles) of 4-chloro-2-(pyridine-3-yl)-1,3-thiazol-5-amine hydrochloride and 200 mLs of anhydrous methylene chloride. The resulting suspension was cooled to 15° C., and 5.98 g (76 mmoles) of pyridine was added at a rate that maintained the temperature below 20° C. 1.85 g (15.11 mmoles) of N,N-dimethylpyridin-4-amine was added in one portion and the resulting yellow solution was stirred at 5° C. for 10 minutes. A solution of 2-methyl-3-(methylthio)propanoyl chloride (5.54 g 36.3 mmoles) in 25 mLs of methylene chloride was added dropwise at a rate that maintained the temperature below 15° C. The reaction was stirred at ambient temperature for 12 hours, than poured into 200 mLs of water. The target was extracted with methylene chloride (3×100 mLs) and the combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes to yield a yellow oil (5.4 g, 55%): 1H NMR (400 MHz, CDCl3) δ 9.12 (dd, J=2.3, 0.8 Hz, 1H), 9.00 (s, 1H), 8.64 (dd, J=4.8, 1.6 Hz, 1H), 8.17 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 7.37 (ddd, J=8.0, 4.9, 0.8 Hz, 1H), 3.00-2.57 (m, 3H), 2.17 (s, 3H), 1.38 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.68, 155.24, 150.55, 146.75, 132.81, 129.26, 127.62, 124.99, 123.80, 40.85, 37.98, 17.46, 16.45. To a dry 500 ml round bottom flask equipped with magnetic stirrer thermometer, addition funnel, and nitrogen inlet maintained the temperature below 20° C that maintained the temperature below 15° C The reaction was stirred at ambient temperature for 12 hours The target was extracted with methylene chloride (3×100 mLs) the combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs) The organic extract was dried over anhydrous magnesium sulfate filtered concentrated under vacuum on a rotary evaporator The crude product was purified by silica gel flash chromatography eluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, reflux condensor, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-amine hydrochloride (20.0 g, 72.4 mmol green solid) and dichloromethane (150 mL). To this suspension was added pyridine (14.32 g, 181 mmol, 2.5 eq) (portionwise over 1 min to form a dark green-black solution. To this solution was added DMAP (4.4 g, 36 mmol) followed by 2-methyl-3-methylthiopropanoyl chloride (16.5 g, 108.6 mmol), which was added portionwise over 1 minute. The reaction exotherm went from 20° C. to 31° C. during the addition of the acid chloride. The reaction was heated to 35° C. for 10 hours then cooled to 25° C. for 14 h. To the dark brown reaction mixture was added dichloromethane (200 mL) and the solution was transferred to a 500 mL separatory funnel. The solution was washed with water (100 mL) and the layers were separated. The brown aqueous layers was extracted with dichloromethane (50 mL) and the dark brown dichloromethane extracts combined, washed with brine (100 mL), dried (MgSO4), filtered and rotary evaporated. This gave 30.49 g (74% pure by HPLC at 254 nm) of a crude black oil. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (23.2 g, 89%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1). Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer reflux condensor, and nitrogen inlet to form a dark green-black solution was added portionwise over 1 minute then cooled to 25° C. for 14 h the solution was transferred to a 500 mL separatory funnel The solution was washed with water (100 mL) the layers were separated The brown aqueous layers was extracted with dichloromethane (50 mL) washed with brine (100 mL) dried (MgSO4) filtered The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes)

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

実験手順: To a solution of (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-methylamine (200 mg, 0.88 mmol) in dichloroethane (2 mL) was added pyridine (83 mg, 1.05 mmol), N,N-dimethylaminopyridine (54 mg, 0.44 mmol) followed by 2-methyl-3-methylsulfanyl-propionyl chloride (160 mg, 1.05 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction was diluted with water and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a light yellow solid (250 mg, 84%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.75 (d, J=3.8 Hz, 1H), 8.28-8.15 (m, 1H), 7.45 (dd, J=8.0, 4.9 Hz, 1H), 3.32 (s, 3H), 2.99-2.72 (m, 2H), 2.50 (d, J=7.5 Hz, 1H), 2.06 (d, J=2.5 Hz, 3H), 1.31-1.14 (m, 3H); ESIMS m/z 342 (M+1). the mixture was extracted with dichloromethane The organic layer was dried over Na2SO4 filtered concentrated The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes)

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

実験手順: To a solution of (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-methylamine (200 mg, 0.88 mmol) in dichloroethane (2 mL) was added pyridine (83 mg, 1.05 mmol), N,N-dimethylaminopyridine (54 mg, 0.44 mmol) followed by 2-methyl-3-methylsulfanyl-propionyl chloride (160 mg, 1.05 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction was diluted with water and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a light yellow solid (250 mg, 84%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.75 (d, J=3.8 Hz, 1H), 8.28-8.15 (m, 1H), 7.45 (dd, J=8.0, 4.9 Hz, 1H), 3.32 (s, 3H), 2.99-2.72 (m, 2H), 2.50 (d, J=7.5 Hz, 1H), 2.06 (d, J=2.5 Hz, 3H), 1.31-1.14 (m, 3H); ESIMS m/z 342 (M+1). the mixture was extracted with dichloromethane The organic layer was dried over Na2SO4 filtered concentrated The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes)

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

実験手順: To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, and nitrogen inlet was added 4-chloro-N-methyl-2-(pyridin-3-yl)thiazol-5-amine (22 g, 97 mmol) and dichloromethane (250 mL). The suspension was stiffed at room temperature while pyridine (8.48 g, 107 mmol) and DMAP (1.20 g, 9.75 mmol) were added. To this suspension was added 2-methyl-3-(methylthio)propanoyl chloride (17.8 g, 117 mmol) over 5 minutes. During the addition all solids went into solution and the reaction was exothermic from 20° C. to 30° C. The reaction was stirred at ambient temperature for 16 h. The mixture was checked by HPLC(YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA over 20 Min @ 1.0 ml/min) which showed complete conversion of all starting material. The reaction mixture was diluted with dichloromethane and water was then added. The mixture was poured into a separatory funnel with dichloromethane and water and the layers separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to afford 33.6 g of a dark oil. The oil was purified on an ISCO Combiflash Rf (330 g silica gel cartridge, mobile phase A=hexane, B=ethyl acetate, gradient 0% B to 100% B over 20 minutes). The fractions were collected into 25 mL test tubes. The tubes containing the desired product were combined and the solvent removed by rotary evaporation. This afforded 22.8 g of a thick yellow liquid in 68.4% isolated yield. The entire sample crystallized and hexane (200 mL) was added to give a slurry. The slurry was vacuum filtered and the solid allowed to air dry. This gave N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N,2-dimethyl-3-(methylthio)propanamide as an off-white solid; mp 75-80° C.; 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.4 Hz, 1H), 8.73 (d, J=3.8 Hz, 1H), 8.34-8.09 (m, 1H), 7.43 (dd, J=7.9, 4.9 Hz, 1H), 3.30 (s, 3H), 3.06-2.70 (m, 2H), 2.49 (d, J=7.4 Hz, 1H), 2.04 (s, 3H), 1.21 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 175.22, 162.37, 151.91, 146.53, 136.46, 134.64, 133.35, 127.98, 124.27, 37.47, 36.71, 36.47, 17.56, 15.44; Anal. Calcd. for C14H16ClN3OS2: C, 49.18; H, 4.72; N, 12.29; S, 18.76. Found: C, 49.04: H, 4.68; N, 12.29; S, 18.68. To a dry 500 ml round bottom flask equipped with magnetic stirrer were added During the addition all solids was exothermic from 20° C. to 30° C was then added the layers separated The organic phase was washed with brine dried over anhydrous magnesium sulfate filtered rotary evaporated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, reflux condensor, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-amine hydrochloride (20.0 g, 72.4 mmol green solid) and dichloromethane (150 mL). To this suspension was added pyridine (14.32 g, 181 mmol, 2.5 eq) (portionwise over 1 min to form a dark green-black solution. To this solution was added DMAP (4.4 g, 36 mmol) followed by 2-methyl-3-methylthiopropanoyl chloride (16.5 g, 108.6 mmol), which was added portionwise over 1 minute. The reaction exotherm went from 20° C. to 31° C. during the addition of the acid chloride. The reaction was heated to 35° C. for 10 hours then cooled to 25° C. for 14 h. To the dark brown reaction mixture was added dichloromethane (200 mL) and the solution was transferred to a 500 mL separatory funnel. The solution was washed with water (100 mL) and the layers were separated. The brown aqueous layers was extracted with dichloromethane (50 mL) and the dark brown dichloromethane extracts combined, washed with brine (100 mL), dried (MgSO4), filtered and rotary evaporated. This gave 30.49 g (74% pure by HPLC at 254 nm) of a crude black oil. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (23.2 g, 89%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1). Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer reflux condensor, and nitrogen inlet to form a dark green-black solution was added portionwise over 1 minute then cooled to 25° C. for 14 h the solution was transferred to a 500 mL separatory funnel The solution was washed with water (100 mL) the layers were separated The brown aqueous layers was extracted with dichloromethane (50 mL) washed with brine (100 mL) dried (MgSO4) filtered The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes)

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

実験手順: To a solution of (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-methylamine (200 mg, 0.88 mmol) in dichloroethane (2 mL) was added pyridine (83 mg, 1.05 mmol), N,N-dimethylaminopyridine (54 mg, 0.44 mmol) followed by 2-methyl-3-methylsulfanyl-propionyl chloride (160 mg, 1.05 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction was diluted with water and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a light yellow solid (250 mg, 84%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.75 (d, J=3.8 Hz, 1H), 8.28-8.15 (m, 1H), 7.45 (dd, J=8.0, 4.9 Hz, 1H), 3.32 (s, 3H), 2.99-2.72 (m, 2H), 2.50 (d, J=7.5 Hz, 1H), 2.06 (d, J=2.5 Hz, 3H), 1.31-1.14 (m, 3H); ESIMS m/z 342 (M+1). the mixture was extracted with dichloromethane The organic layer was dried over Na2SO4 filtered concentrated The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes)