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To a solution of2-amino-4-bromobenzenethiol (544 mg,2.67 mmol)in acetic acid (26.7mL)was added triphosgene (530 mg,1.79 mmol). The mixture was heated at reflux for 18 h.After cooling to room temperature,the solution was partially concentrated under reducedpressure,water was added,and the resulting precipitate was removed via filtration,and washed with aqueous NaOH (1.0 M). The filtrate was acidified with HCl (2 N)to pH 2,and placed in arefrigerator for 12 h. The resulting precipitate was filtered,washed with water,and dried underreduced pressure to give the title compound (94 mg,15percent)as a while powder that required nofurther purification. 1H NMR (400 MHz,DMSO-d6)8 12.07 (s,1H),7.55 (d,J = 8.4 Hz,1H),5 7.30 (d,J = 8.0 Hz,1H),7.24 (s,1H).
20 g
at 0℃; for 18 h; Reflux
Zn (70 g, 1077 mmol) was added to a solution of B (28 g, 120 mmol) in AcOH (500 ml). Reaction mixture was stirred at 65°C for 15 h under nitrogen to give C, monitored by TLC. The mixture was cooled to room temperature, and triphosgene (25 g, 84 mmol) added slowly at 0°C. Mixture was refluxed for 18 h, monitored by TLC. Solution was then concentrated and hydrolyzed with water. Yellow solid was collected to give D (20 g, 73percent, over two steps).
Reference:
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 10151 - 10171
[2] Patent: WO2017/205536, 2017, A2, . Location in patent: Page/Page column 83; 84
[3] Patent: WO2014/190199, 2014, A1, . Location in patent: Paragraph 00285
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 24h;
a) 5-Bromo-3-(2-methoxyethyl)benzo[d]thiazol-2(3H)-one5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.502 g) were stirred in DMF (7 mL) at room temperature and l-bromo-2-methoxyethane (0.408 mL) was added. The mixture was stirred for 24 h. The mixture was poured onto water and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 10% ethyl acetate in isohexane afforded the subtitle compound as a colourless solid (0.73 g). <n="98"/>1H NMR (399.824 MHz, CDCl3) delta 7.36 (t, J = 1.0 Hz, IH), 7.28 - 7.26 (m, 2H), 4.09 (t, J 5.5 Hz, 2H), 3.68 (t, J = 5.5 Hz, 2H), 3.34 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃;
5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.502 g) were stirred in DMF (7 mL) at room temperature and l-bromo-2-methoxyethane (0.408 mL) was added. The mixture was stirred for 24 h. The mixture was poured onto water and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 10% ethyl acetate in ohexane afforded the sub-titled compound as a colourless solid (0.73 g). 1H NMR (399.824 MHz, CDCl3) delta 7.36 (t, IH), 7.28 - 7.26 (m, 2H), 4.09 (t, 2H), 3.68 (t, 2H), 3.34 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 48h;
a) 5-Bromo-3-(2-hydroxyethyl)benzo[d]thiazol-2(3H)-one5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.5 g) were stirred in DMF (7 mL) at room temperature and 2-bromoethanol (0.4 mL) added. The mixture was stirred for 48 h. The mixture was poured onto water and acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 25% ethyl acetate in isohexane afforded the subtitle compound as a colourless solid (0.540 g). 1H NMR (399.826 MHz, d6-DMSO) delta 7.64 (d, J = 1.8 Hz, IH), 7.61 (d, J = 8.5 Hz, IH), 7.36 (dd, J = 8.5, 1.8 Hz, IH), 4.91 (t, J = 5.8 Hz, IH), 4.01 (t, J = 5.5 Hz, 2H), 3.64 (q, J = 5.6 Hz, 2H).
To a solution of2-amino-4-bromobenzenethiol (544 mg,2.67 mmol)in acetic acid (26.7mL)was added triphosgene (530 mg,1.79 mmol). The mixture was heated at reflux for 18 h.After cooling to room temperature,the solution was partially concentrated under reducedpressure,water was added,and the resulting precipitate was removed via filtration,and washed with aqueous NaOH (1.0 M). The filtrate was acidified with HCl (2 N)to pH 2,and placed in arefrigerator for 12 h. The resulting precipitate was filtered,washed with water,and dried underreduced pressure to give the title compound (94 mg,15%)as a while powder that required nofurther purification. 1H NMR (400 MHz,DMSO-d6)8 12.07 (s,1H),7.55 (d,J = 8.4 Hz,1H),5 7.30 (d,J = 8.0 Hz,1H),7.24 (s,1H).
20 g
for 18h;Reflux;
Zn (70 g, 1077 mmol) was added to a solution of B (28 g, 120 mmol) in AcOH (500 ml). Reaction mixture was stirred at 65C for 15 h under nitrogen to give C, monitored by TLC. The mixture was cooled to room temperature, and triphosgene (25 g, 84 mmol) added slowly at 0C. Mixture was refluxed for 18 h, monitored by TLC. Solution was then concentrated and hydrolyzed with water. Yellow solid was collected to give D (20 g, 73%, over two steps).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 120.0℃; for 4h;Inert atmosphere;
To a solution of D (5 g, 22 mmol) in DMF (15 ml) was added Zn(CN)2 (5 g, 43 mmol), Pd(dppf)Cl2 (1.5 g, 2.2 mmol) and Pd2(dba)3 (0.6 g, 1.1 mmol). Reaction mixture was stirred at 120C for 4 h under nitrogen, monitored by TLC. The mixture was extracted with EtOAc, washed with water and brine, then dried and concentrated. Crude material was purified by column chromatography (silica gel, EtOAc:PE=l :4) to give E (1.0 g, 26%) as a yellow solid.
3-[3-(N-benzyl-N-methylamino)propyl]-5-bromobenzothiazolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate; In N,N-dimethyl-formamide; at 70.0℃;
General procedure: One equivalent of appropriate heterocyclic derivative was dissolved in DMF. Three equivalents of potassium carbonate and 1.2 equivalent of the appropriate 3-chloropropan-1-amine derivative were added. The resulting mixture was heated at 70C until disappearance of the starting material. The reaction was monitored by TLC. After 24-96 h, the solvent was removed under reduced pressure, and water added to the residue. The crude product was extracted with dichloromethane. The combined organic fractions were washed with water and dried over magnesium sulphate. Purification by thick layer chromatography or column chromatography was performed.
To a solution of <strong>[199475-45-1]5-bromo-3H-1,3-benzothiazol-2-one</strong> (94.4 mg,0.410 mmol)in water(2.1 mL)was added NaOH (16.4 mg,0.410 mmol)and then dimethyl sulfate (62.1 mg,0.492mmol). After stirring at room temperature for 3 h,the resulting precipitate was filtered,washedwith water,and dried under reduced pressure to give the title compound (89.3 mg,89%)as awhite powder that required no further purification. 1H NMR (400 MHz,CDCl3)8 7.32- 7.2915 (m,2H),7.20 (dd,J = 1.5,0.6 Hz,1H),3.45 (s,3H).
In tetrahydrofuran at 25 - 50℃; for 2h; Inert atmosphere;
6MMM.1 Step 1: Synthesis of 5-bromobenzo[d]thiazol-2(3H)-one
2-Amino-4-bromo-benzenethiol (30 g, 147.00 mmol) was dissolved in dry THF (500 mL) under argon. To the above solution di(imidazol-1-yl)methanone (26.5 g, 163.43 mmol) was added in one portion under argon and the reaction mixture was stirred under argon at 25°C for 1 hr (slightly exothermic reaction observed). Then the reaction mixture was stirred at 50°C for 1 hr (after the exothermic reaction passed), and then cooled down and concentrated in vacuum. The residue was diluted with water (300 ml), the precipitate was filtered, washed with water (3*50 ml) and dried in vacuum to afford 5-bromo-3H-1,3-benzothiazol-2-one (33.5 g, 145.60 mmol, 99.05% yield) as white solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 7.23 (s, 1H), 7.31 (d, 1H), 7.55 (s, 1H), 12.05 (bds, 1H). LCMS(ESI): [M]+ m/z: calcd 230.2; found 231.2; Rt = 1.083 min
99.05%
In tetrahydrofuran at 25 - 50℃; for 2h; Inert atmosphere;
6MMM.1 Step 1: Synthesis of 5-bromobenzo[d]thiazol-2(3H)-one
2-Amino-4-bromo-benzenethiol (30 g, 147.00 mmol) was dissolved in dry THF (500 mL) under argon. To the above solution di(imidazol-1-yl)methanone (26.5 g, 163.43 mmol) was added in one portion under argon and the reaction mixture was stirred under argon at 25°C for 1 hr (slightly exothermic reaction observed). Then the reaction mixture was stirred at 50°C for 1 hr (after the exothermic reaction passed), and then cooled down and concentrated in vacuum. The residue was diluted with water (300 ml), the precipitate was filtered, washed with water (3*50 ml) and dried in vacuum to afford 5-bromo-3H-1,3-benzothiazol-2-one (33.5 g, 145.60 mmol, 99.05% yield) as white solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 7.23 (s, 1H), 7.31 (d, 1H), 7.55 (s, 1H), 12.05 (bds, 1H). LCMS(ESI): [M]+ m/z: calcd 230.2; found 231.2; Rt = 1.083 min