2-sulfanylacetonitrile

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Under ice cooling and stirring, 0.44 g of mercaptoacetonitrile was added to 2.22 g of 11-hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 45 dissolved in a mixed solution of 20 ml of trifluoroacetic acid and 10 ml of methylene chloride and the mixture was stirred at the same temperature for 1.5 hours. The residue obtained by condensing the reaction mixture under reduced pressure was dissolved in ethyl acetate and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution and dried over anhydrous sodium sulfate. The viscous residue obtained by removing the solvent was crystallized from diethyl ether to obtain 1.23 g of the title compound. obtained in Reference example 45 the mixture was stirred at the same temperature for 1.5 hours The residue obtained by condensing the reaction mixture under reduced pressure the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution a saturated saline solution and dried over anhydrous sodium sulfate The viscous residue obtained by removing the solvent was crystallized from diethyl ether

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (R)-4-(5-Bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (5.1 g, 11.1 mmol, Eq: 1.00) and 1,1,3,3-tetramethylguanidine (1.91 g, 2.09 ml, 16.6 mmol, Eq: 1.5) in DMF (77.3 ml) was added at 23° C. 2-mercaptoacetonitrile (1.22 g, 16.6 mmol, Eq: 1.5) dropwise. The reaction mixture was stirred at 23° C. for 16 hours. All volatiles were was evaporated at high vacuum and the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours. Sat. NaHCO3 solution was slowly added (pH=8), then extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane to give (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetonitrile (5.2 g, 10.9 mmol, 98.3% yield) as a light brown oil. MS (ISP): m/z=453.0 [M+H]+ and 455.2 [M+2+H]+. All volatiles were was evaporated at high vacuum the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours Sat. NaHCO3 solution was slowly added (pH=8) extracted twice with dichloromethane The combined organic layers were dried over Na2SO4 filtered evaporated The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (R)-4-(5-Bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (5.1 g, 11.1 mmol, Eq: 1.00) and 1,1,3,3-tetramethylguanidine (1.91 g, 2.09 ml, 16.6 mmol, Eq: 1.5) in DMF (77.3 ml) was added at 23° C. 2-mercaptoacetonitrile (1.22 g, 16.6 mmol, Eq: 1.5) dropwise. The reaction mixture was stirred at 23° C. for 16 hours. All volatiles were was evaporated at high vacuum and the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours. Sat. NaHCO3 solution was slowly added (pH=8), then extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane to give (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetonitrile (5.2 g, 10.9 mmol, 98.3% yield) as a light brown oil. MS (ISP): m/z=453.0 [M+H]+ and 455.2 [M+2+H]+. All volatiles were was evaporated at high vacuum the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours Sat. NaHCO3 solution was slowly added (pH=8) extracted twice with dichloromethane The combined organic layers were dried over Na2SO4 filtered evaporated The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane

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

実験手順: Under ice cooling and stirring, 0.44 g of mercaptoacetonitrile was added to 2.22 g of 11-hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 45 dissolved in a mixed solution of 20 ml of trifluoroacetic acid and 10 ml of methylene chloride and the mixture was stirred at the same temperature for 1.5 hours. The residue obtained by condensing the reaction mixture under reduced pressure was dissolved in ethyl acetate and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution and dried over anhydrous sodium sulfate. The viscous residue obtained by removing the solvent was crystallized from diethyl ether to obtain 1.23 g of the title compound. obtained in Reference example 45 the mixture was stirred at the same temperature for 1.5 hours The residue obtained by condensing the reaction mixture under reduced pressure the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution a saturated saline solution and dried over anhydrous sodium sulfate The viscous residue obtained by removing the solvent was crystallized from diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Mercaptoacetonitrile (1.03 g, 14.1 mmol) was added dropwise to a solution of (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5,5-dioxide (4.1 g, 9.37 mmol) and 1,1,3,3-tetramethylguanidine (1.62 g, 14.1 mmol) in N,N-dimethylformamide (55 ml) at room temperature. The reaction mixture was then stirred at 60° C. for 12 hours. For the workup, the solvent was evaporated at reduced pressure, and the residue was dissolved in dichloromethane (50 ml). After addition of sulfuric acid (20%; 50 ml, 185 mmol) and stirring overnight, the mixture was poured onto a saturated solution of sodium hydrogencarbonate followed by the extraction (2×) with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The {rel-(3R,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ylsulfanyl}-acetonitrile (3.92 g, 97% yield) was obtained as a light brown oil. MS (ISP): m/z=431.2 [M+H]+. For the workup, the solvent was evaporated at reduced pressure the residue was dissolved in dichloromethane (50 ml) stirring overnight followed by the extraction (2×) with dichloromethane The combined organic layers were dried over sodium sulphate evaporated The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent

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

実験手順: To an ice cold solution of furoyl chloride (4.0 ml; 0.04 mol) in ether (100 ml) is added dropwise a freshly prepared solution of pyridine (3.24 ml; 0.04 mol) in 1 N mercaptoacetonitrile (40 ml; 0.04 mol). After the addition is completed, the mixture is allowed to stir at room temperature overnight. The reaction mixture is then washed with water, saturated sodium bicarbonate solution, saturated brine, dried over sodium sulfate, and is concentrated in vacuo. The residue (6.0 g) is filtered through a 25 g column of silica gel and eluted with methylene chloride. The methylene chloride eluent is diluted with hexane, cooled and filtered to yield 4.3 g (64%) of title product, an orange solid, melting point 76°-78° C. Recrystallization from methylene chloride-hexane affords 3.7 g product, as a pale orange solid, melting point 77°-78° C. After the addition The reaction mixture is then washed with water, saturated sodium bicarbonate solution, saturated brine dried over sodium sulfate is concentrated in vacuo The residue (6.0 g) is filtered through a 25 g column of silica gel eluted with methylene chloride The methylene chloride eluent is diluted with hexane cooled filtered

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (R)-4-(5-Bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (5.1 g, 11.1 mmol, Eq: 1.00) and 1,1,3,3-tetramethylguanidine (1.91 g, 2.09 ml, 16.6 mmol, Eq: 1.5) in DMF (77.3 ml) was added at 23° C. 2-mercaptoacetonitrile (1.22 g, 16.6 mmol, Eq: 1.5) dropwise. The reaction mixture was stirred at 23° C. for 16 hours. All volatiles were was evaporated at high vacuum and the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours. Sat. NaHCO3 solution was slowly added (pH=8), then extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane to give (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetonitrile (5.2 g, 10.9 mmol, 98.3% yield) as a light brown oil. MS (ISP): m/z=453.0 [M+H]+ and 455.2 [M+2+H]+. All volatiles were was evaporated at high vacuum the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours Sat. NaHCO3 solution was slowly added (pH=8) extracted twice with dichloromethane The combined organic layers were dried over Na2SO4 filtered evaporated The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane

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

実験手順: Under ice cooling and stirring, 0.44 g of mercaptoacetonitrile was added to 2.22 g of 11-hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 45 dissolved in a mixed solution of 20 ml of trifluoroacetic acid and 10 ml of methylene chloride and the mixture was stirred at the same temperature for 1.5 hours. The residue obtained by condensing the reaction mixture under reduced pressure was dissolved in ethyl acetate and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution and dried over anhydrous sodium sulfate. The viscous residue obtained by removing the solvent was crystallized from diethyl ether to obtain 1.23 g of the title compound. obtained in Reference example 45 the mixture was stirred at the same temperature for 1.5 hours The residue obtained by condensing the reaction mixture under reduced pressure the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution a saturated saline solution and dried over anhydrous sodium sulfate The viscous residue obtained by removing the solvent was crystallized from diethyl ether