3-methyl-3-sulfanylbutan-1-ol

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Methyl-3-sulfanylbutan-1-ol (Sweetman et al, J. Med. Chem. 14:868 (1971), the disclosure of which is incorporated by reference herein in its entirety) (5 g, 42 mmol) and pyridine (3.6 mL, 43 mmol) were dissolved in methylene chloride (50 mL) and cooled to −78° C. Acetyl chloride (3.1 mL, 43 mmol) was added dropwise. The solution was kept cold for 30 min then allowed to warm to room temperature. Stirring was continued for 1.5 hours. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and brine, and dried over sodium sulfate. Evaporation of the solvent gave 6.6 g of the title compound which was used without further purification. 1H-NMR (CDCl3): δ1.41 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 2.03 (s, 3H), 2.21 (s, 1H), 4.25 (t, J=7.1 Hz, 2H). to warm to room temperature was continued for 1.5 hours washed with 1 N HCl and brine dried over sodium sulfate Evaporation of the solvent

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Methyl-3-sulfanylbutan-1-ol (Sweetman et al, J. Med. Chem. 14:868 (1971), the disclosure of which is incorporated by reference herein in its entirety) (5 g, 42 mmol) and pyridine (3.6 mL, 43 mmol) were dissolved in methylene chloride (50 mL) and cooled to −78° C. Acetyl chloride (3.1 mL, 43 mmol) was added dropwise. The solution was kept cold for 30 min then allowed to warm to room temperature. Stirring was continued for 1.5 hours. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and brine, and dried over sodium sulfate. Evaporation of the solvent gave 6.6 g of the title compound which was used without further purification. 1H-NMR (CDCl3): δ1.41 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 2.03 (s, 3H), 2.21 (s, 1H), 4.25 (t, J=7.1 Hz, 2H). to warm to room temperature was continued for 1.5 hours washed with 1 N HCl and brine dried over sodium sulfate Evaporation of the solvent

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

実験手順: To a solution of 4-fluoro-3-nitrobenzoic acid (2 g, 10.80 mmol) in DMF (50 ml) was added potassium carbonate (3.73 g, 27.0 mmol), and 3-mercapto-3-methylbutan-1-ol (1.450 ml, 11.88 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture had turned yellow over night. The DMF was removed under reduced pressure and the resulting slurry was diluted with EtOAc (100 mL) and extracted with H2O (100 mL). The aqueous layer was then treated with conc. HCl until a precipitate formed. The mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over Na2SO4 and concentrated in vacuo. The product was isolated as a yellow solid and used without further purification. The reaction mixture had turned yellow over night The DMF was removed under reduced pressure the resulting slurry was diluted with EtOAc (100 mL) extracted with H2O (100 mL) The aqueous layer was then treated with conc. HCl until a precipitate formed The mixture was extracted with EtOAc (3×100 mL) the combined organics were dried over Na2SO4 concentrated in vacuo The product was isolated as a yellow solid used without further purification

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of compound 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (60 mg, 0.129 mmoles) in 1,4-dioxane (1.5 mL) in a screw-capped vial under argon are added diisopropylethylamine (33 μL, 0.142 mmole), 3-mercapto-3-methylbutan-1-ol (20 μL, 0.193 mmole), bis(dibenzilideneacetone)palladium(0) (4 mg, 6.4 μmole), Xantphos (4 mg, 6.4 μmole). The reaction mixture is heated at 110° C. overnight. As the reaction is not complete, bis(dibenzilideneacetone)Palladium(0) (4 mg, 6.4 μmole), Xantphos (4 mg, 6.4 μmole), diisopropylethylamine (33 μL, 0.142 mmole), 3-mercapto-3-methylbutan-1-ol (20 μL, 0.193 mmole) are added to the reaction mixture. After one overnight at 120° C., water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (95:5) to (90:10) to afford 3-methyl-3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylsulfanyl}-butan-1-ol. The aqueous phase is extracted three times with CH2Cl2 The organic phase is dried over magnesium sulphate filtered the solvent is removed under reduced pressure The residue is purified by silica gel chromatography

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Methyl-3-sulfanylbutan-1-ol (Sweetman et al, J. Med. Chem. 14:868 (1971), the disclosure of which is incorporated by reference herein in its entirety) (5 g, 42 mmol) and pyridine (3.6 mL, 43 mmol) were dissolved in methylene chloride (50 mL) and cooled to −78° C. Acetyl chloride (3.1 mL, 43 mmol) was added dropwise. The solution was kept cold for 30 min then allowed to warm to room temperature. Stirring was continued for 1.5 hours. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and brine, and dried over sodium sulfate. Evaporation of the solvent gave 6.6 g of the title compound which was used without further purification. 1H-NMR (CDCl3): δ1.41 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 2.03 (s, 3H), 2.21 (s, 1H), 4.25 (t, J=7.1 Hz, 2H). to warm to room temperature was continued for 1.5 hours washed with 1 N HCl and brine dried over sodium sulfate Evaporation of the solvent