* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Thionyl chloride (200mL, 2.76mol) was slowly added dropwise to a solution of 9 (100g, 703mmol) in MeOH (500mL). After stirring at reflux for 3h, the mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, washed with water, saturated aqueous NaHCO3 and brine, and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure to give 105g (96percent) of 10 as a brown oil: 1H NMR (400MHz, CDCl3) δ 7.38 (d, J=5.4Hz, 1H), 6.98 (d, J=5.4Hz, 1H), 3.85 (s, 3H), 2.74 (s, 3H); MS (ESI) m/z: 157 (M+H)+.
78%
at 0℃; for 4 h; Reflux
2 (14.00 g, 98.60 mmol) was dissolved inmethanol (60 ml). Concentrated sulfuric acid (30 ml) was added dropwise at 0°C. The reaction mixture was stirred for 4 h at reflux, thenwas cooled to room temperature, and the solvent was evaporated under reducedpressure. The residue was partitioned between CH2Cl2 (200 ml)and H2O (60 ml). The organic phase was washed with H2O (50 ml), saturated aqueous sodium bicarbonate solution (50ml) and saturated brine solution (50 ml),dried over Na2SO4, and filtrated, then the solvent wasevaporated under reduced pressure to give 3 (12.00 g, 78.0percent) as acolorless viscous oil. 1H NMR (400 MHz,CDCl3)δ 7.38 (d, J =5.5 Hz, 1H), 6.98 (d, J = 5.1, 1H), 3.85 (s, 3H), 2.73(s, 3H). MS (EI)m/z: 156 (M+).
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 269 - 294
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5417 - 5422
[3] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 471 - 476
[4] Journal of Medicinal Chemistry, 1995, vol. 38, # 24, p. 4806 - 4820
[5] Patent: US2012/101137, 2012, A1, . Location in patent: Page/Page column 14
2
[ 40018-26-6 ]
[ 1830-54-2 ]
[ 865187-80-0 ]
[ 53562-51-9 ]
Yield
Reaction Conditions
Operation in experiment
51%
With lithium bromide In 1,4-dioxane for 20 h; Reflux
A solution of dimethyl acetone-1,3-dicarboxylate (7) (51.4 g, 0.296 mol) in 1,4-dioxane (75 mL) and then LiBr (28.2 g, 0.325 mol) were added to a stirred suspension of 2,5-dihydroxy-1,4-dithiane (30.0 g, 0.197 mol) in 1,4-dioxane (300 mL). The mixture was stirred at reflux for 20 h. The mixture was filtered into a separating funnel and extracted with ethyl acetate (500 mL) and water (70 mL). The water layer was re-extracted with ethyl acetate (2.x.250 mL) and the combined organic layers were washed with aq HCl (500 mL, 1 M), aq NaHCO3 (5percent), aq NaOH (500 mL, percent10) and then with brine (500 mL). The solution was dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography (350 g) eluting with hexane/ethyl acetate (7:2) and then (5:2) to give monoester 10 as the first fraction. The desired diester 9 was isolated as the second fraction.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; acetone; at 80℃; for 18.0h;
Methyl 2-methylthiophene-3-carboxylate (0.915 g, 5.86 mmol) was dissolved in CCl4 (30 mL). NBS (1.04 g, 5.86 mmol) was added followed by AIBN (0.4 mL, 12% in acetone). The mixture was heated at 80 C. for 18 h, followed by workup to provide methyl 2-(bromomethyl)thiophene-3-carboxylate (1.35 g, 98%). MS (M+1) 236.1.
49%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile);
Example 23; Three side chains were prepared by NBS bromination of methyl group, which were indicated as the following table:
Thionyl chloride (200mL, 2.76mol) was slowly added dropwise to a solution of 9 (100g, 703mmol) in MeOH (500mL). After stirring at reflux for 3h, the mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, washed with water, saturated aqueous NaHCO3 and brine, and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure to give 105g (96%) of 10 as a brown oil: 1H NMR (400MHz, CDCl3) delta 7.38 (d, J=5.4Hz, 1H), 6.98 (d, J=5.4Hz, 1H), 3.85 (s, 3H), 2.74 (s, 3H); MS (ESI) m/z: 157 (M+H)+.
78%
With sulfuric acid; at 0℃; for 4.0h;Reflux;
2 (14.00 g, 98.60 mmol) was dissolved inmethanol (60 ml). Concentrated sulfuric acid (30 ml) was added dropwise at 0C. The reaction mixture was stirred for 4 h at reflux, thenwas cooled to room temperature, and the solvent was evaporated under reducedpressure. The residue was partitioned between CH2Cl2 (200 ml)and H2O (60 ml). The organic phase was washed with H2O (50 ml), saturated aqueous sodium bicarbonate solution (50ml) and saturated brine solution (50 ml),dried over Na2SO4, and filtrated, then the solvent wasevaporated under reduced pressure to give 3 (12.00 g, 78.0%) as acolorless viscous oil. 1H NMR (400 MHz,CDCl3)delta 7.38 (d, J =5.5 Hz, 1H), 6.98 (d, J = 5.1, 1H), 3.85 (s, 3H), 2.73(s, 3H). MS (EI)m/z: 156 (M+).
With thionyl chloride; for 3.0h;Reflux;
2-Methylthiophene-3-carboxylic acid (100 g) was dissolved in methanol (500 mL), thionyl chloride (200 mL) was slowly added dropwise thereto, and reflux was conducted for 3 hours. The reaction liquid was concentrated under a reduced pressure, water was added to the obtained residue, and extraction was conducted by using methylene chloride. The organic phase was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. Filtration was conducted, and the filtrate was then concentrated under a reduced pressure to give the title compound (105 g).1H-NMR (CDCl3) delta (ppm): 2.74 (3H, s), 3.85 (3H, s), 6.98 (1H, d, J=5.1 Hz), 7.38 (1H, d, J=5.5 Hz).
With potassium carbonate; In water; acetone; pentane;
Methyl (2-methyl) 3-thiophenecarboxylate To a solution of 3.30 g (23.2 mmol) of 2-methyl-3-thiophenecarboxylic acid in 100 ml of acetone was added 16.04 g (116.1 mmol) of anhydrous potassium carbonate and 16.47 g (7.2 ml, 116.1 mmol) of methyl iodide. The reaction mixture was allowed to stir at room temperature for 20.25 hours. A white precipitate formed. The white precipitate was filtered, washed with ethyl ether and discarded. The filtrate was concentrated in vacuo, partitioned between 250 ml of water and 250 ml of pentane and the layers separated. The organic phase was washed with a saturated solution of Na2 SO3, dried over Na2 SO4, filtered and concentrated by rotary evaporation to give the title compound as a yellow oil which was used without further purification. PMR (CDCl3): d 2.74 (3H, s), 3.85 (3H, s), 6.98 (1H, d, J=5.4 Hz), 7.38 (1H, d, 5.4 Hz).
With lithium bromide; In 1,4-dioxane; for 20.0h;Reflux;
A solution of dimethyl acetone-1,3-dicarboxylate (7) (51.4 g, 0.296 mol) in 1,4-dioxane (75 mL) and then LiBr (28.2 g, 0.325 mol) were added to a stirred suspension of 2,5-dihydroxy-1,4-dithiane (30.0 g, 0.197 mol) in 1,4-dioxane (300 mL). The mixture was stirred at reflux for 20 h. The mixture was filtered into a separating funnel and extracted with ethyl acetate (500 mL) and water (70 mL). The water layer was re-extracted with ethyl acetate (2×250 mL) and the combined organic layers were washed with aq HCl (500 mL, 1 M), aq NaHCO3 (5%), aq NaOH (500 mL, %10) and then with brine (500 mL). The solution was dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography (350 g) eluting with hexane/ethyl acetate (7:2) and then (5:2) to give monoester 10 as the first fraction. The desired diester 9 was isolated as the second fraction.
5-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-2-(2-cyanopyridin-5-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one[ No CAS ]
5-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-2-(2-methoxypyridin-5-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one[ No CAS ]
5-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-2-(3-fluoropyridin-5-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one[ No CAS ]
5-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-2-(2-methoxypyrimidin-5-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one[ No CAS ]
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