N-(2-chloroethyl)-N-propan-2-ylpropan-2-amine;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Compound 107 (1 g., 2.64 mmol), 2-(diisopropylamino) ethyl chloride hydrochloride (2.64 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0–10% methanol in ethylacetate gradient to yield 409 mg (30%) of pale yellow solids. M.P. 110–117° C. 1H NMR (DMSO-d6): δ 0.93 (s, 12H), 2.40 (s, 3H), 2.59 (m, 2H), 3.01 (m, 2H), 3.61 (m, 4H), 3.91 (m, 4H), 4.15 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 506 (M+1). Anal. (C28H35N5O2S) C, H, N. The solution was cooled The solids formed were filtered washed by water dried The crude product was purified by flash chromatography eluting with 0–10% methanol in ethylacetate gradient

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 2-(diisoproplyamino)ethyl chloride hydrochloride (0.50 g) are added. The reaction mixture is heated to 90° C. for 2 h, then allowed to stir at room temperature overnight. A drop of water is added and the mixture is heated for 20 h. An additional equivalent of 2-(diisoproplyamino)ethyl chloride hydrochloride (0.25 g, 1.25 mmol) is added and the mixture is heated at 100° C. for 5 h, and then stirred at room temperature overnight. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-2% MeOH/CHCl3) gave 0.45 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.22 g of the title compound as a solid. the mixture is heated for 20 h the mixture is heated at 100° C. for 5 h stirred at room temperature overnight an oily solid formed which is isolated by decanting the liquid Column chromatography (elution with 1-2% MeOH/CHCl3)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 2-(diisoproplyamino)ethyl chloride hydrochloride (0.50 g) are added. The reaction mixture is heated to 90° C. for 2 h, then allowed to stir at room temperature overnight. A drop of water is added and the mixture is heated for 20 h. An additional equivalent of 2-(diisoproplyamino)ethyl chloride hydrochloride (0.25 g, 1.25 mmol) is added and the mixture is heated at 100° C. for 5 h, and then stirred at room temperature overnight. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-2% MeOH/CHCl3) gave 0.45 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.22 g of the title compound as a solid. the mixture is heated for 20 h the mixture is heated at 100° C. for 5 h stirred at room temperature overnight an oily solid formed which is isolated by decanting the liquid Column chromatography (elution with 1-2% MeOH/CHCl3)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.515 g) is dissolved in DMF (10 mL), and K2CO3 (0.778 g) and diisoproplyaminoethyl chloride-hydrochloride (0.56 g) are added. The reaction mixture is heated to 95° C. for 14 h, then allowed to stir at room temperature overnight. The mixture is then poured into H2O and an oil formed, which is isolated by decanting the liquid. The oil is dissolved in MeOH/CH2Cl2, and etheral HCl is added to adjust the pH to 2. The mixture is concentrated in vacuo to give the title compound as the hydrochloride salt. an oil formed which is isolated by decanting the liquid The oil is dissolved in MeOH/CH2Cl2 etheral HCl is added The mixture is concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Compound 107 (1 g, 2.64 mmol), 2-(diisopropylamino)ethyl chloride hydrochloride (2.64 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient to yield 409 mg (30%) of pale yellow solids. M.P. 110-117° C. 1H NMR (DMSO-d6): δ 0.93 (s, 12H), 2.40 (s, 3H), 2.59 (m, 2H), 3.01 (m, 2H), 3.61 (m, 4H), 3.91 (m, 4H), 4.15 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 506 (M+1). Anal. (C28H35N5O2S) C,H, N. The solution was cooled The solids formed were filtered washed by water dried The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Compound 107 (1 g, 2.64 mmol), 2-(diisopropylamino)ethyl chloride hydrochloride (2.64 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient to yield 409 mg (30%) of pale yellow solids. M.P. 110-117° C. 1H NMR (DMSO-d6): δ 0.93 (s, 12H), 2.40 (s, 3H), 2.59 (m, 2H), 3.01 (m, 2H), 3.61 (m, 4H), 3.91 (m, 4H), 4.15 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 506 (M+1). Anal. (C28H35N5O2S) C,H, N. The solution was cooled The solids formed were filtered washed by water dried The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By using the 7-bromo-5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out to obtain 7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin having a melting point of 94°-97° C. (yield: 13.1%).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By using the 7-bromo-5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out to obtain 7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin having a melting point of 94°-97° C. (yield: 13.1%).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3.00 g of 5-methoxyisatin and 3.39 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry N,N-dimethylformamide was added 1.36 g of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. The mixture was stirred for 1 hour at room temperature and then heated at 80° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform) and recrystallized from hexane to obtain 3.33 g of 1-(2-diisopropylaminoethyl)-5-methoxyisatin having a melting point of 81°-82.5° C. cooling The mixture was stirred for 1 hour at room temperature The reaction mixture was concentrated under reduced pressure, and water was added to the residue The mixture was extracted with ethyl acetate the ethyl acetate layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified with silica gel flash column chromatography (eluent: chloroform) recrystallized from hexane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3.00 g of 5-methoxyisatin and 3.39 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry N,N-dimethylformamide was added 1.36 g of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. The mixture was stirred for 1 hour at room temperature and then heated at 80° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform) and recrystallized from hexane to obtain 3.33 g of 1-(2-diisopropylaminoethyl)-5-methoxyisatin having a melting point of 81°-82.5° C. cooling The mixture was stirred for 1 hour at room temperature The reaction mixture was concentrated under reduced pressure, and water was added to the residue The mixture was extracted with ethyl acetate the ethyl acetate layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified with silica gel flash column chromatography (eluent: chloroform) recrystallized from hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By using methyl 7-isatincarboxylate and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 7 was carried out to obtain methyl 1-(2-diisopropylaminoethyl)-7-isatincarboxylate in an oil (yield: 94.6%).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By using 5-acetamidoisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 7 was carried out to obtain 5-acetamido-1-(2-diisopropylaminoethyl)isatin having a melting point of 187°-190° C. (yield: 77.0%, recrystallizing solvent: ethyl acetate-hexane).