N-methylpentan-1-amine

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

Procedure: To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylpentylamine (333 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=4 Hz, 2H), 7.36 (s, 1H), 3.90 (s, 3H), 3.47 (s, 2H), 3.13 (t, J=9 Hz, 3H), 2.39 (s, 2H), 2.34 (d, J=8 Hz, 2H), 2.18 (s, 3H), 1.45 (m, 5H), 1.32 (m, 2H). filtered the reaction mixture is stirred at room temperature for 5 h washed with 1 N hydrochloric acid, and saturated sodium bicarbonate dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes)

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

Procedure: A solution of 3.9 g of m-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 10 ml of n-hexane was added to 4 g of N-methyl-N-pentylamine and the mixture was allowed to stand overnight. The precipitated crystals were separated by filtration and washed thoroughly with n-hexane to obtain 5.4 g of the title compound. The precipitated crystals were separated by filtration washed thoroughly with n-hexane

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

Procedure: A solution of 3.9 g of m-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 10 ml of n-hexane was added to 4 g of N-methyl-N-pentylamine and the mixture was allowed to stand overnight. The precipitated crystals were separated by filtration and washed thoroughly with n-hexane to obtain 5.4 g of the title compound. The precipitated crystals were separated by filtration washed thoroughly with n-hexane

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

Procedure: To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylpentylamine (333 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=4 Hz, 2H), 7.36 (s, 1H), 3.90 (s, 3H), 3.47 (s, 2H), 3.13 (t, J=9 Hz, 3H), 2.39 (s, 2H), 2.34 (d, J=8 Hz, 2H), 2.18 (s, 3H), 1.45 (m, 5H), 1.32 (m, 2H). filtered the reaction mixture is stirred at room temperature for 5 h washed with 1 N hydrochloric acid, and saturated sodium bicarbonate dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (14 cc.) is added over the course of 8 minutes to a 2.5N solution (42 cc.) of phosgene in methylcyclohexane, cooled to -10° C., and a solution of N-methylpentylamine (13.7 cc.) in toluene (50 cc.) is then added whilst maintaining the temperature at -10° C. The mixture is stirred for 1 hour at +5° C. The insoluble material is then filtered off and washed with toluene (80 cc.). The organic solutions are dried over calcium chloride (10 g.). After filtration, the solvents are evaporated under reduced pressure (40 mm.Hg). The residue is distilled under reduced pressure to give N-methyl-N-pentylcarbamoyl chloride (5.6 g.), b.p. 120-125° C./40 mm.Hg. whilst maintaining the temperature at -10° C The insoluble material is then filtered off washed with toluene (80 cc.) The organic solutions are dried over calcium chloride (10 g.) After filtration the solvents are evaporated under reduced pressure (40 mm.Hg) The residue is distilled under reduced pressure

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

Procedure: The title compound was prepared from N-methylpentan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.41 (br s, 1H), 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.23 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.61 (br, 4H), 2.39 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 1.23 (m, 4H), 0.83 (t, 3H); MS (ESI): 522.1.

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

Procedure: To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylpentylamine (333 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=4 Hz, 2H), 7.36 (s, 1H), 3.90 (s, 3H), 3.47 (s, 2H), 3.13 (t, J=9 Hz, 3H), 2.39 (s, 2H), 2.34 (d, J=8 Hz, 2H), 2.18 (s, 3H), 1.45 (m, 5H), 1.32 (m, 2H). filtered the reaction mixture is stirred at room temperature for 5 h washed with 1 N hydrochloric acid, and saturated sodium bicarbonate dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (14 cc.) is added over the course of 8 minutes to a 2.5N solution (42 cc.) of phosgene in methylcyclohexane, cooled to -10° C., and a solution of N-methylpentylamine (13.7 cc.) in toluene (50 cc.) is then added whilst maintaining the temperature at -10° C. The mixture is stirred for 1 hour at +5° C. The insoluble material is then filtered off and washed with toluene (80 cc.). The organic solutions are dried over calcium chloride (10 g.). After filtration, the solvents are evaporated under reduced pressure (40 mm.Hg). The residue is distilled under reduced pressure to give N-methyl-N-pentylcarbamoyl chloride (5.6 g.), b.p. 120-125° C./40 mm.Hg. whilst maintaining the temperature at -10° C The insoluble material is then filtered off washed with toluene (80 cc.) The organic solutions are dried over calcium chloride (10 g.) After filtration the solvents are evaporated under reduced pressure (40 mm.Hg) The residue is distilled under reduced pressure

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

Procedure: The title compound was prepared from N-methylpentan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.41 (br s, 1H), 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.23 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.61 (br, 4H), 2.39 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 1.23 (m, 4H), 0.83 (t, 3H); MS (ESI): 522.1.

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

Procedure: To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylpentylamine (333 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=4 Hz, 2H), 7.36 (s, 1H), 3.90 (s, 3H), 3.47 (s, 2H), 3.13 (t, J=9 Hz, 3H), 2.39 (s, 2H), 2.34 (d, J=8 Hz, 2H), 2.18 (s, 3H), 1.45 (m, 5H), 1.32 (m, 2H). filtered the reaction mixture is stirred at room temperature for 5 h washed with 1 N hydrochloric acid, and saturated sodium bicarbonate dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes)

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

Procedure: This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and methyl-pentyl-amine. MS (ESI): 442.4 (MH+).

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

Procedure: Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and N-methylamylamine (29 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (33 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.5-7.15 (m, 6H), 7.04 (d, 1H), 5.02 (m, 1H), 4.81 (s, 2H), 4.28 (m, 1H), 3.25-2.7 (m, 9H), 1.10-1.5 (m, 15H), 0.89 (t, 3H); HRMS m/z 613.2982 (calc. of monoisotopic mass for C32H43N3O9 gives 613.2999). Synthesis according to Method C with HPLC purification