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With sodium hydride In 1-methyl-pyrrolidin-2-one at 130℃; for 2 h;
To a solution of (5-Bromo-2,4-difluoro-phenyl)-thiourea (0.75 g, 2.80 mmol) in NMP (5.0 mL) was added NaH (0.17 g, 4.21 mmol, 60percent dispersion in oil) portion wise. The reaction mixture was then heated at 13O0C for 2 h. The reaction mixture was then poured onto crushed ice and extracted with EtOAc (3 x 50 mL). The combined organics was evaporated to get the crude residue that was purified over silica gel (100-200 M, 12percent EtOAc-Hexane) to obtain the desired compound (0.36 g, 52percent). 1H- NMR (400 MHz, DMSO-d6): δ 7.57 (d, J= 6.40 Hz, 1 H), 7.66 (br s, 2H) and 7.79 (d, 8.80 Hz, 1 H).
52%
With sodium hydride In 1-methyl-pyrrolidin-2-one; mineral oil at 130℃; for 2 h;
To a solution of ii (0.75 g, 2.80 mmol) in NMP (5.0 mL) was added NaH (0.17 g, 4.21 mmol, 60percent dispersion in oil) portion wise. The mixture was heated at 130° C. for 2 h. and then poured onto crushed ice and extracted with EtOAc (3*50 mL). The combined organics were evaporated. Purification by chromatography on silica eluting with 12percent EtOAc-Hexane gave iii (0.36 g, 52percent). 1H-NMR (400 MHz, DMSO-d6): δ 7.57 (d, J=6.40 Hz, 1H), 7.66 (br s, 2H) and 7.79 (d, 8.80 Hz, 1H).
Stage #1: at 10 - 100℃; Stage #2: With ammonia In water
1 -(3-Bromo-4-fluorophenyi)thiourea (3.77g, 15.1 mmo.) was solved in acetic acid (156 mL) and cooled to I CCC. Bromine (3.63 g, 22.7 mmol) in acetic acid (69 mL) was added and after 15 minutes the mixture was heated to 100°C for 2 hours. A solution of sodium bisulphite was added and the mixture was heated shortly to 100 under vigorous stirring while the mixture lost its bromine colour. The mixture was concentrated under reduced pressure, the residue suspended in aqueous ammonia and the alkaline mixture was extracted multiple times with dichioromethane. The organic extracts were concentrated and solved in methanol (40 mL). Water (60 mL) was added and the forming precipitate collected by filtration. The precipitate was purified by chromatography on silica gel (ethyl acetate in hexane 12 to 50percent) to give 0.90 g (23percent) of 5-bromo-6-fluoro-1,3-benzothiazol-2-amine: H NMR (300 MHz, DMSO-cfe) δ = 7.57 (d, 1 H), 7.67 (s, 2H), 7.78 (d, 1 H) ppm.
To a solution of <strong>[1160789-91-2]5-bromo-6-fluoro-benzothiazol-2-ylamine</strong> (0.36 g, 1.45 mmol) in 1 ,4- dioxane (25.0 mL) was added ethyl isocyanate (0.69 ml_, 8.74 mmol) and the resulting reaction mixture was heated at 8O0C for 15 h. After the completion of the reaction (TLC monitoring) the solvent was evaporated. The residue thus obtained was stirred with water at 6O0C for 5 h. The solution was then filtered and washed with ether to get the title compound (0.30 g, 69%). 1H-NMR (400 MHz, DMSO-d6): delta 1.08 (t, J= 6.80 Hz, 3H), 3.17 (m, 2H), 6.69 (br s, 1 H), 7.92 (d, J= 6.40 Hz, 1 H), 8.0 (d, J= 8.40 Hz, 1 H) and 10.86 (br s, 1 H).
69%
In 1,4-dioxane; at 80℃; for 15h;
To a solution of iii (0.36 g, 1.45 mmol) in 1,4-dioxane (25.0 mL) was added ethyl isocyanate (0.69 mL, 8.74 mmol) and the mixture heated at 80 C. for 15 h. The solvent was evaporated and the residue stirred with H2O at 60 C. for 5 h. The solution was filtered and washed with Et2O to obtain Intermediate 13 (0.30 g, 69%).
With sodium hydride; In 1-methyl-pyrrolidin-2-one; at 130℃; for 2h;
To a solution of (5-Bromo-2,4-difluoro-phenyl)-thiourea (0.75 g, 2.80 mmol) in NMP (5.0 mL) was added NaH (0.17 g, 4.21 mmol, 60% dispersion in oil) portion wise. The reaction mixture was then heated at 13O0C for 2 h. The reaction mixture was then poured onto crushed ice and extracted with EtOAc (3 x 50 mL). The combined organics was evaporated to get the crude residue that was purified over silica gel (100-200 M, 12% EtOAc-Hexane) to obtain the desired compound (0.36 g, 52%). 1H- NMR (400 MHz, DMSO-d6): delta 7.57 (d, J= 6.40 Hz, 1 H), 7.66 (br s, 2H) and 7.79 (d, 8.80 Hz, 1 H).
52%
With sodium hydride; In 1-methyl-pyrrolidin-2-one; mineral oil; at 130℃; for 2h;
To a solution of ii (0.75 g, 2.80 mmol) in NMP (5.0 mL) was added NaH (0.17 g, 4.21 mmol, 60% dispersion in oil) portion wise. The mixture was heated at 130 C. for 2 h. and then poured onto crushed ice and extracted with EtOAc (3*50 mL). The combined organics were evaporated. Purification by chromatography on silica eluting with 12% EtOAc-Hexane gave iii (0.36 g, 52%). 1H-NMR (400 MHz, DMSO-d6): delta 7.57 (d, J=6.40 Hz, 1H), 7.66 (br s, 2H) and 7.79 (d, 8.80 Hz, 1H).
To 5-bromo-6-fluoro-1 ,3-benzothiazol-2-amine (590 mg, 2.39 mmo.) in 1- methyipyrrolidin (3 mL) was added copper(i)cyanide and the mixture was heated to 200 for 3 hours. After cooling to room temperatur e a sodium bicarbonate solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated NH4CI-solution and brine, dried over sodium sulphate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate in diehioromethane 2 to 40% ) and finally triturated with dichloromethane to yield 127 mg (25%) 2-amino-6-fluoro-1,3-benzothiazole-5-carbonitrile as a white solid: 1H NMR (300 MHz, DMSO-d6) delta = 7.76 (d, 1 H), 7.84 (s, 2H), 7.93 (d, 2H) ppm.
1 -(3-Bromo-4-fluorophenyi)thiourea (3.77g, 15.1 mmo.) was solved in acetic acid (156 mL) and cooled to I CCC. Bromine (3.63 g, 22.7 mmol) in acetic acid (69 mL) was added and after 15 minutes the mixture was heated to 100C for 2 hours. A solution of sodium bisulphite was added and the mixture was heated shortly to 100 under vigorous stirring while the mixture lost its bromine colour. The mixture was concentrated under reduced pressure, the residue suspended in aqueous ammonia and the alkaline mixture was extracted multiple times with dichioromethane. The organic extracts were concentrated and solved in methanol (40 mL). Water (60 mL) was added and the forming precipitate collected by filtration. The precipitate was purified by chromatography on silica gel (ethyl acetate in hexane 12 to 50%) to give 0.90 g (23%) of 5-bromo-6-fluoro-1,3-benzothiazol-2-amine: H NMR (300 MHz, DMSO-cfe) delta = 7.57 (d, 1 H), 7.67 (s, 2H), 7.78 (d, 1 H) ppm.
To a stirred solution of 3-bromo-4-fluoroaniline (4.0 g, 21 mmol) in acetonitrile (50 mL) was added ammonium thiocyanate (2.1 g, 27 mmol). After 20 min, benzyltrimethylammonium tribromide (8.2 g, 21 mmol) was added in portions and the reaction was stirred at ambient temperature for 16 hrs. The reaction mixture was concentrated in vacuo and the resulting residue was neutralized with saturated NaHCCb solution and stirred for 1.5 hrs. A pale yellow precipitate formed which was filtered and washed with water (10 mL) and dried under reduced pressure. Compound 26a and Compound 26a' (4.5 g, 87 % yield) were collected as a 1 : 1 mixture. MS m/z = 248.8 (M+H). 1H NMR (500MHz, CD3OD) d 7.53 (d, J = 6.2 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 4.2, 8.8 Hz, 1H), 7.1 1 (t, J = 8.8 Hz, 1H).
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