ethyl 2-(methylamino)benzoate

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Methyl-2-carboethoxyaniline (5.0 g, 28 mmol) was treated with 2-chloroethylisocyanate (2.86 mL, 28 mmol) at reflux in toluene for 18 hours. The reaction was cooled to 25° C., and the crystalline product was collected by filtration to yield the intermediate 1-methyl-3-(2-chloroethyl)-quinazoline-2-4-dione. The intermediate quinazolinedione (0.53 g, 2.2 mmol) and cis-6-methoxy-2,3,3a,4,5,9b-[1H]-benz[e]isoindole (0.38 g, 1.87 mmol) were combined in acetonitrile (3 mL) and diisopropylethylamine (0.8 mL) was added. The reaction mixture was heated at reflux for 18 hours. The resulting product was converted to its HCl salt and recrystallized from acetone:ether to yield the title compound (0.30 g, 40%) as a white solid. m.p. 215°-217° C. (dec). 1H NMR (300 MHz, CDCl3) of the free base δ 8.2 (dd, 1H), 7.7 (dt, 1H), 7.1- 7.32 (m, 3H), 6.75 (t, 2H), 4.48 (m, 3H), 4.1-4.3 (m, 2H), 3.81 (s, 3H), 3.68 (m, 1H), 3.6 (s, 3H), 3.35-3.5 (m, 2H), 2.87-4.3 (m, 2H), 2.72-2.87 (m, 2H), 2.52-2.65 (m, 1H), 1.88-2.0 (m, 1H), 1.55-1.7 (m, 1H). MS (DCI/NH3) m/e 406 (M+H)+. Anal calcd for C24H27N3O3.HCl. H2O: C, 62.67; H, 6.57; N, 9.14. Found: C, 62.52; H, 6.51; N, 9.03. the crystalline product was collected by filtration

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

Procedure: A mixture of 21 g. of N-benzylproline and 300 ml. of benzene is stirred and 12 g. of thionyl chloride is added dropwise. The reaction mixture is heated on the steam bath for 2 hours, and 18 g. of ethyl N-methylanthranilate are added. The mixture is heated at reflux temperature for 6 hours, washed with dilute sodium hydroxide and concentrated. The residue is purified by partition chromatography and ethyl N-(N-benzyl-2-pyrrolidinylcarbonyl)-N-methylanthranilate is obtained. A mixture of 21 g The reaction mixture is heated on the steam bath for 2 hours The mixture is heated at reflux temperature for 6 hours washed with dilute sodium hydroxide concentrated The residue is purified by partition chromatography

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Methyl-2-carboethoxyaniline (5.0 g, 28 mmol) was treated with 2-chloroethylisocyanate (2.86 mL, 28 mmol) at reflux in toluene for 18 hours. The reaction was cooled to 25° C., and the crystalline product was collected by filtration to yield the intermediate 1-methyl-3-(2-chloroethyl)-quinazoline-2-4-dione. The intermediate quinazolinedione (0.53 g, 2.2 mmol) and cis-6-methoxy-2,3,3a,4,5,9b-[1H]-benz[e]isoindole (0.38 g, 1.87 mmol) were combined in acetonitrile (3 mL) and diisopropylethylamine (0.8 mL) was added. The reaction mixture was heated at reflux for 18 hours. The resulting product was converted to its HCl salt and recrystallized from acetone:ether to yield the title compound (0.30 g, 40%) as a white solid. m.p. 215°-217° C. (dec). 1H NMR (300 MHz, CDCl3) of the free base δ 8.2 (dd, 1H), 7.7 (dt, 1H), 7.1- 7.32 (m, 3H), 6.75 (t, 2H), 4.48 (m, 3H), 4.1-4.3 (m, 2H), 3.81 (s, 3H), 3.68 (m, 1H), 3.6 (s, 3H), 3.35-3.5 (m, 2H), 2.87-4.3 (m, 2H), 2.72-2.87 (m, 2H), 2.52-2.65 (m, 1H), 1.88-2.0 (m, 1H), 1.55-1.7 (m, 1H). MS (DCI/NH3) m/e 406 (M+H)+. Anal calcd for C24H27N3O3.HCl. H2O: C, 62.67; H, 6.57; N, 9.14. Found: C, 62.52; H, 6.51; N, 9.03. the crystalline product was collected by filtration