1,2,3,6,7,11b-hexahydropyrazino[2,1-a]isoquinolin-4-one

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: Further embodiments disclosed herein provide a process for the preparation of Praziquantel of formula I by cyclisation of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide using an acid in the presence of a solvent to obtain 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline; and acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline with cyclohexanoylchloride in presence of a base and a solvent to obtain Praziquantel. Further embodiments disclosed herein provide a process

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

実験手順: Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).

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

実験手順: 1,2,3,6,7,11b-Hexahydro-pyrazino[2,1-a]isoquinolin-4-one (3.03 g, 15.0 mmol) was added to a solution of lithium aluminum hydride (1.14 g, 30.0 mmol) in tetrahydrofuran (63 ml) and the mixture was refluxed for 6 hours. Water (1.2 ml), 15% aqueous sodium hydroxide (1.2 ml) and water (3.2 ml) were added sequentially to the ice-cooled solution, and filtration of the precipitate and removal of the solvent under reduced pressure afforded 1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline (2.77 g, 98%). the mixture was refluxed for 6 hours cooled solution, and filtration of the precipitate and removal of the solvent under reduced pressure

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

実験手順: 1,2,3,6,7,11b-Hexahydro-pyrazino[2,1-a]isoquinolin-4-one (3.03 g, 15.0 mmol) was added to a solution of lithium aluminum hydride (1.14 g, 30.0 mmol) in tetrahydrofuran (63 ml) and the mixture was refluxed for 6 hours. Water (1.2 ml), 15% aqueous sodium hydroxide (1.2 ml) and water (3.2 ml) were added sequentially to the ice-cooled solution, and filtration of the precipitate and removal of the solvent under reduced pressure afforded 1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline (2.77 g, 98%). the mixture was refluxed for 6 hours cooled solution, and filtration of the precipitate and removal of the solvent under reduced pressure

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

実験手順: 2-Chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (332 mg, 1.5 mmol) was added to the solution of 1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (313 mg, 1.55 mmol), triethylamine (0.223 ml, 1.6 mmol) in N,N-dimethylformamide (8 ml) and the mixture was stirred for 4 hour and stood overnight. Ice-water was added to the solution and resulting precipitate was collected by filtration and washed with water and then dried to afford 2-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (555 mg, 96%). Treatment with 4N hydrogen chloride in ethyl acetate yielded corresponding hydrogen chloride salt. stood overnight resulting precipitate was collected by filtration washed with water dried

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

実験手順: 2-(2,2-Dimethoxy-ethylamino)-N-phenethyl-acetamide hydrochloride (8.77 g, 29.0 mmol) was added to the ice-cooled sulfuric acid (8.8 ml) and the mixture was stirred for 3.5 hours at room temperature. Ice-water was added to the solution after cooling by ice and the resulting solution was extracted with dichloromethane after adjusted to pH 12 with 20% aqueous sodium hydroxide. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvents were removed under reduced pressure. Recrystallization of the residue with hexane-ethyl acetate afforded 1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (4.38 g, 75%). after cooling by ice the resulting solution was extracted with dichloromethane after adjusted to pH 12 with 20% aqueous sodium hydroxide The organic layer was washed with brine dried with magnesium sulfate the solvents were removed under reduced pressure Recrystallization of the residue with hexane-ethyl acetate

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

実験手順: 2-(2,2-Dimethoxy-ethylamino)-N-phenethyl-acetamide hydrochloride (8.77 g, 29.0 mmol) was added to the ice-cooled sulfuric acid (8.8 ml) and the mixture was stirred for 3.5 hours at room temperature. Ice-water was added to the solution after cooling by ice and the resulting solution was extracted with dichloromethane after adjusted to pH 12 with 20% aqueous sodium hydroxide. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvents were removed under reduced pressure. Recrystallization of the residue with hexane-ethyl acetate afforded 1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (4.38 g, 75%). after cooling by ice the resulting solution was extracted with dichloromethane after adjusted to pH 12 with 20% aqueous sodium hydroxide The organic layer was washed with brine dried with magnesium sulfate the solvents were removed under reduced pressure Recrystallization of the residue with hexane-ethyl acetate

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

実験手順: Further embodiments disclosed herein provide a process for the preparation of Praziquantel of formula I by cyclisation of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide using an acid in the presence of a solvent to obtain 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline; and acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline with cyclohexanoylchloride in presence of a base and a solvent to obtain Praziquantel. Further embodiments disclosed herein provide a process

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

実験手順: Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).

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

実験手順: Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).