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With copper(ll) bromide; isopentyl nitrite In acetonitrile at 20℃; for 1.5 h;
A mixture of intermediate 3 (8 g, 39.8 mmol), copper (II) bromide (10.43 g, 46.68 mmol) and 3-methyl-l-nitrosooxy-butane (6.8 g, 58.35 mmol) in ACN (100 mL) was stirred at room temperature for 1.5 hours. The solvent was evaporated in vacuo. The residue thus obtained was dissolved in AcOEt and washed with H20. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo to yield 5 g (55percent) of intermediate 4 that was used in the next step without further purification.
36%
With copper(ll) bromide In tetrahydrofuran at 20℃; for 12 h;
Step ii: 2-bromo-6,7-dihydrothiazolo[5,4-clpyridin-4(5H)-one To a 50 mL round bottom flask, were added 2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)- one (0.4 g, 0.0023 mol) and THF (10 mL). To the same flask, amyl nitrite (1.6 mL) and copper (II) bromide (0.4 g) were added. The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get crude product. The crude product was purified by column chromatography using 60-120 silica gel and 50 percent ethyl acetate in hexane to get the title compound [0.2 g, 36 percent]. LC-MS: 232.0 [M+H]+.
With copper(ll) bromide; isopentyl nitrite In acetonitrile at 20℃; for 1.5 h;
A mixture of intermediate 4 (8 g, 39.8 mmol), copper (II) bromide (10.43 g, 46.68 mmol) and 3-methyl-l-nitrosooxy-butane (6.8 g, 58.35 mmol) in ACN (100 mL) was stirred at room temperature for 1.5 hours. The solvent was evaporated in vacuo. The residue thus obtained was dissolved in AcOEt and washed with H20. The organic layer was separated, dried (Na2S04), filtered and the solvent evaporated in vacuo to yield 5 g (55percent) of intermediate 6 that was used in the next step without further purification.
Reference：
[1] Patent: WO2011/73347, 2011, A1, . Location in patent: Page/Page column 34
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 18, p. 7243 - 7259
[3] Patent: US2012/252800, 2012, A1, . Location in patent: Page/Page column 15
With copper(ll) bromide; isopentyl nitrite; In acetonitrile; at 20℃; for 1.5h;
A mixture of intermediate 3 (8 g, 39.8 mmol), copper (II) bromide (10.43 g, 46.68 mmol) and 3-methyl-l-nitrosooxy-butane (6.8 g, 58.35 mmol) in ACN (100 mL) was stirred at room temperature for 1.5 hours. The solvent was evaporated in vacuo. The residue thus obtained was dissolved in AcOEt and washed with H20. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo to yield 5 g (55%) of intermediate 4 that was used in the next step without further purification.
36%
With copper(ll) bromide; In tetrahydrofuran; at 20℃; for 12h;
Step ii: 2-bromo-6,7-dihydrothiazolo[5,4-clpyridin-4(5H)-one To a 50 mL round bottom flask, were added 2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)- one (0.4 g, 0.0023 mol) and THF (10 mL). To the same flask, amyl nitrite (1.6 mL) and copper (II) bromide (0.4 g) were added. The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get crude product. The crude product was purified by column chromatography using 60-120 silica gel and 50 % ethyl acetate in hexane to get the title compound [0.2 g, 36 %]. LC-MS: 232.0 [M+H]+.
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 50℃; under 18751.9 Torr;
A mixture of triethylamine (17.2 g, 170 mmol) and Iota,Gamma- bis(diphenylphosphino)ferrocenedichloro palladium (II) (2.0 g, 2.7 mmol) in THF (300 mL) was added to a solution of intermediate 4 (7.5 g, 23.6 mmol) in MeOH (300 mL). The mixture was stirred at 50C overnight under CO atmosphere (2.5 MPa). The reaction mixture was cooled, filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in MeOH 100/1). The desired fractions were collected and the solvents evaporated in vacuo to yield a yellow solid that was crystallized from AcOEt to yield 4.5 g (21%) of intermediate 5.
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; In 1,4-dioxane; at 80℃; for 2h;Inert atmosphere;
To a solution of intermediate 6 (2.33 g, 10 mmol), phenylacetylene (2.0 g, 20 mmol) and triethylamine (4.5 g, 45 mmol) in 1,4-dioxane (50 mL) at room temperature were added [l, -bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.73 g, 1 mmol) and copper (I) iodide (0.75 g, 4 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80C for 2 hours under a nitrogen atmosphere, then cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in AcOEt and washed with H20. The organic layer was separated, dried (Na2S04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/ AcOEt 10: 1 to 1 : 1). The desired fractions were collected and the solvent was evaporated in vacuo to yield compound 3 (0.7 g, 30% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) delta ppm 3.00 (t, J=7.0 Hz, 2 H),3.50 (td, J=7.0, 2.5 Hz, 2 H), 7.44 - 7.57 (m, 3 H), 7.63 - 7.72 (m, 2 H), 8.07 (br.H).
With copper(l) iodide; triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 20 - 80℃; for 2h;Inert atmosphere;
To a solution of intermediate 6 (2.33 g, 10 mmol), phenylacetylene (2.0 g, 20 mmol) and triethylamine (4.5 g, 45 mmol) in 1,4-dioxane (50 mL) at room temperature were added [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.73 g, 1 mmol) and copper (I) iodide (0.75 g, 4 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80 C. for 2 hours under a nitrogen atmosphere, then cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in AcOEt and washed with H2O. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/AcOEt 10:1 to 1:1). The desired fractions were collected and the solvent was evaporated in vacuo to yield compound 3 (0.7 g, 30% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.00 (t, J=7.0 Hz, 2H), 3.50 (td, J=7.0, 2.5 Hz, 2H), 7.44-7.57 (m, 3H), 7.63-7.72 (m, 2H), 8.07 (br. s., 1H).
With copper(ll) bromide; isopentyl nitrite; In acetonitrile; at 20℃; for 1.5h;
A mixture of intermediate 4 (8 g, 39.8 mmol), copper (II) bromide (10.43 g, 46.68 mmol) and 3-methyl-l-nitrosooxy-butane (6.8 g, 58.35 mmol) in ACN (100 mL) was stirred at room temperature for 1.5 hours. The solvent was evaporated in vacuo. The residue thus obtained was dissolved in AcOEt and washed with H20. The organic layer was separated, dried (Na2S04), filtered and the solvent evaporated in vacuo to yield 5 g (55%) of intermediate 6 that was used in the next step without further purification.
With copper(ll) bromide; isopentyl nitrite; In acetonitrile; at 20℃; for 1.5h;
A mixture of intermediate 4 (8 g, 39.8 mmol), copper (II) bromide (10.43 g, 46.68 mmol) and 3-methyl-1-nitrosooxy-butane (6.8 g, 58.35 mmol) in ACN (100 mL) was stirred at room temperature for 1.5 hours. The solvent was evaporated in vacuo. The residue thus obtained was dissolved in AcOEt and washed with H2O. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 5 g (55%) of intermediate 6 that was used in the next step without further purification.
2-bromo-5-ethyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Step iii: 2-bromo-5-ethyl-6J-dihydrothiazolo[5,4-clpyridin-4(5H)-one To a 50 mL round bottom flask, were added 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)- one (0.2 g, 0.00086 mol) and DMF (10 mL). To the same flask, caesium carbonate (0.7 g, 0.0022 mol) and ethyl iodide (0.272 g, 0.00172 mol) were added. The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get crude product. The crude product was purified by column chromatography using 60-120 silica gel and 40 % ethyl acetate in hexane to get the title compound [0.1 g, 45 %]. LC-MS: 261.0 [M+H]+.
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