N,N'-dimethylpropane-1,3-diamine

反応条件: temp:0.00; pressure:0.00; stir:

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: A solution of tris(dibenzylidineacetone)dipalladium (0) (0.016 g, 0.01697 mmol) in tetrahydrofuran under nitrogen atmosphere was treated with triphenylphosphine (0.007 g, 0.0255 mmol). The reaction mixture was stirred for about 20 minutes under a nitrogen atmosphere. A solution of 1-[2-(2,6-dichloroanilino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allyl acetate (Snow et al., 2001) (0.080 g, 0.1697 mmol) in tetrahydrofuran was added to the palladium solution. Triethylamine (0.052 g, 0.509 mmol) and N,N′-dimethyl-1,3-propanediamine (0.087 g, 0.8485 mmol) were added to the reaction solution. The reaction mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Tetrahydrofuran was removed from the reaction mixture under reduced pressure. Acetic acid (0.5 mL) and dimethylformamide (5 mL) were added. The reaction mixture was filtered through a Gelman filter disk and was then purified by preparative HPLC chromatography. The preparative column afforded 0.012 g (14%) of pure 13, 2-(2,6-dichloroanilino)-1,6-dimethyl-7-((E)-3-{methyl[3-(methylamino)propyl]amino}-1-propenyl)-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-9-one. 1H NMR (CDCl3, 400 MHz) δ 7.8572-7.8355 (d, 1H J=8.68 Hz), 7.5408-7.5189 (d, 1H, J=8.76 Hz), 7.399-7.366 (m, 2H), 7.118-7.078 (t, 1H) 6.786-6.746 (m, 1H), 6.312-6.256 (m, 1H), 4.288 (s, 3H), 3.213-3.199 (m, 2H), 2.696-2,663 (t, 2H), 2.518-2.483 (t, 2H), 2.443 (s, 3H), 2.377 (s, 3H), 2.24 (s, 3H), 1.740-1.689 (m, 2H)); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% CH3CN over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), M+ 513.5 and 515.5. The reaction mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere Tetrahydrofuran was removed from the reaction mixture under reduced pressure Acetic acid (0.5 mL) and dimethylformamide (5 mL) were added The reaction mixture was filtered through a Gelman filter disk was then purified by preparative HPLC chromatography

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

実験手順: Benzyl ester (100 mg, 0.0842 mmol) and Pd/C (en) (10 mg) were suspended in methanol (1 ml), and the obtained suspension was stirred in a hydrogen atmosphere at room temperature for 8 hours. Thereafter, the catalyst was filtrated with a filter, and was then washed with methanol. The filtrate was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1−7:3), so as to obtain carboxylic acid (91.2 mg) in a quantitative manner. The thus obtained carboxylic acid (75.9 mg, 0.070 mg) was dissolved in THF (0.5 ml). Thereafter, diisopropylethylamine (32 μl, 0.184 mmol) and p-toluenesulfonyl isocyanate (39 μl, 0.256 mmol) were added thereto in an argon atmosphere, and the obtained mixture was stirred for 1 hour. Thereafter, N,N′-dimethyl-1,3-propanediamine (0.1 ml) was added dropwise to the reaction solution, and a 10% citric acid aqueous solution was then added thereto. An aqueous layer was extracted with chloroform. An organic layer was washed with a saline solution, and it was then dried over sodium sulfate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1), so as to obtain 77.5 mg (87%) of tosylamide. An aqueous layer was extracted with chloroform An organic layer was washed with a saline solution, and it was then dried over sodium sulfate The solvent was distilled away under reduced pressure The residue was purified by silica gel column chromatography (chloroform:methanol=9:1)

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

実験手順: To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 200 milliliters of o-dichlorobenzene was added 10.22 grams (0.10 mole) of N,N'-dimethyl-1,3-propanediamine and the resulting mixture heated under reflux for 21 hours. The reaction mixture was cooled, the solvent decanted therefrom and isopropanol added to the gummy residue to obtain 24.35 grams (59.8 percent yield) of 2-diphenylmethylimino-1,2,3,4,5,6-hexahydro-1,3-dimethylpyrimidine hydroiodide product of m.p., 215°-219° C. After two recrystallizations from methanol-isopropanol, a purified product, m.p. 221° C., was obtained. the resulting mixture heated under reflux for 21 hours The reaction mixture was cooled the solvent decanted isopropanol added to the gummy residue

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

実験手順: To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 200 milliliters of o-dichlorobenzene was added 10.22 grams (0.10 mole) of N,N'-dimethyl-1,3-propanediamine and the resulting mixture heated under reflux for 21 hours. The reaction mixture was cooled, the solvent decanted therefrom and isopropanol added to the gummy residue to obtain 24.35 grams (59.8 percent yield) of 2-diphenylmethylimino-1,2,3,4,5,6-hexahydro-1,3-dimethylpyrimidine hydroiodide product of m.p. 215°-219° C. After two recrystallizations from methanol-isopropanol, a purified product, m.p. 221° C., was obtained. the resulting mixture heated under reflux for 21 hours The reaction mixture was cooled the solvent decanted isopropanol added to the gummy residue

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

実験手順: To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 200 milliliters of o-dichlorobenzene was added 10.22 grams (0.10 mole) of N,N'-dimethyl-1,3-propanediamine and the resulting mixture heated under reflux for 21 hours. The reaction mixture was cooled, the solvent decanted therefrom and isopropanol added to the gummy residue to obtain 24.35 grams (59.8 percent yield) of 2-diphenylmethylimino-1,2,3,4,5,6-hexahydro-1,3-dimethylpyrimidine hydroiodide product of m.p., 215°-219° C. After two recrystallizations from methanol-isopropanol, a purified product, m.p. 221° C., was obtained. the resulting mixture heated under reflux for 21 hours The reaction mixture was cooled the solvent decanted isopropanol added to the gummy residue

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: To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 200 milliliters of o-dichlorobenzene was added 10.22 grams (0.10 mole) of N,N'-dimethyl-1,3-propanediamine and the resulting mixture heated under reflux for 21 hours. The reaction mixture was cooled, the solvent decanted therefrom and isopropanol added to the gummy residue to obtain 24.35 grams (59.8 percent yield) of 2-diphenylmethylimino-1,2,3,4,5,6-hexahydro-1,3-dimethylpyrimidine hydroiodide product of m.p. 215°-219° C. After two recrystallizations from methanol-isopropanol, a purified product, m.p. 221° C., was obtained. the resulting mixture heated under reflux for 21 hours The reaction mixture was cooled the solvent decanted isopropanol added to the gummy residue

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred suspension of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43 (a)) (250 mg) and N,N′-dimethyl-1,3-propanediamine (0.80 mL) in acetonitrile (3 mL) was heated at 100° C. in a microwave for 2 hours after which it was cooled to room temperature and concentrated. The residue was purified by recrystallisation (methanol:ethyl acetate). The resultant product was converted to the dihydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (110 mg). was cooled to room temperature concentrated The residue was purified by recrystallisation (methanol:ethyl acetate) Recrystallisation (methanol/ethyl acetate)

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

実験手順: Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-4-(trifluoromethyl)-cyclohexaneacetamide (Example 8 (c)) (150 mg) and N,N′-dimethyl-1,3-propanediamine (450 mg). The product was converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (40 mg). Prepared Recrystallisation (methanol/ethyl acetate)

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

実験手順: Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-4-(trifluoromethyl)-cyclohexaneacetamide (Example 8 (c)) (150 mg) and N,N′-dimethyl-1,3-propanediamine (450 mg). The product was converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (40 mg). Prepared Recrystallisation (methanol/ethyl acetate)