1-benzylimidazolidine-2,4-dione

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

Procedure: In a solvent mixture of 250 ml of acetic acid and 40 ml of ethyl acetate was dispersed 190 g of 1-benzylhydantoin and the mixture was refluxed under heating with stirring. To the mixture was added dropwise 164 g of bromine over a period of one hour, and the mixture was refluxed under heating for 30 minutes. The solvent was distilled off under a reduced pressure and the residue was allowed to stand for cooling. To the residue were added dropwise an aqueous sodium bicarbonate solution prepared by dissolving 53 g of sodium bicarbonate in 400 ml of water and then 200 ml of water. The reaction vessel was cooled with water and the crystals thus-deposited were collected by filtration, washed with water and dried to obtain 182 g of 5-hydroxy-1-benzylhydantoin as colorless crystals. the mixture was refluxed under heating the mixture was refluxed under heating for 30 minutes The solvent was distilled off under a reduced pressure for cooling To the residue were added dropwise an aqueous sodium bicarbonate solution prepared the crystals thus-deposited were collected by filtration washed with water dried

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

Procedure: 1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and isocyanatomethylcyclohexane (87.8 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 36.8 mg (21%), M+H+: 330.18.

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

Procedure: 1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and isocyanatocyclohexane (79 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 22 mg (13%), M+H+: 316.18.

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

Procedure: 1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatopentane (71.4 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 15 mg (9%), M+H+: 304.18.

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

Procedure: 1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatopentane (71.4 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 15 mg (9%), M+H+: 304.18.

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatohexane (80.3 mg, 0.63 mmol) and, if required, a catalytic amount of 4-dimethylaminopyridine were dissolved in 10 ml of toluene and 0.5 ml of pyridine and stirred at 115° C. for 6 h. Then a further 80 mg of 1-isocyanatohexane were added, and the mixture was stirred at 115° C. for a further 6 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and H2O, and the org. phases were washed twice with water, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 11.3 mg (7%), M+H+:318.14. The reaction mixture was concentrated phases were washed twice with water concentrated purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA)

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatohexane (80.3 mg, 0.63 mmol) and, if required, a catalytic amount of 4-dimethylaminopyridine were dissolved in 10 ml of toluene and 0.5 ml of pyridine and stirred at 115° C. for 6 h. Then a further 80 mg of 1-isocyanatohexane were added, and the mixture was stirred at 115° C. for a further 6 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and H2O, and the org. phases were washed twice with water, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 11.3 mg (7%), M+H+:318.14. The reaction mixture was concentrated phases were washed twice with water concentrated purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA)

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

Procedure: The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.

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

Procedure: The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%. in only low yields

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

Procedure: The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.

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

Procedure: The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.

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

Procedure: 500 ml of acetic acid was added to 57 g of 1-benzylhydantoin and, while maintaining at 80° C. with stirring, 50.3 g of bromine was dropwise added thereto. After completion of the dropwise addition, the solution was further stirred for 2 hours. The reaction solution was then cooled and, while cooling with ice, 56 g of ethylene glycol was added thereto. After stirring for 30 minutes, the solution was further stirred for 3 hours at room temperature. One liter of water was added to the reaction solution, followed by extraction with 500 ml of ethyl acetate. The extract was further washed twice with 500 ml of water. The thus obtained ethyl acetate solution was dried with sodium sulfate, concentrated, and purified by silica gel chromatography to obtain 52 g of 1-benzyl-5-(2-hydroxyethoxy)hydantoin. (Yield: 74%) After completion of the dropwise addition the solution was further stirred for 2 hours The reaction solution was then cooled was added After stirring for 30 minutes the solution was further stirred for 3 hours at room temperature followed by extraction with 500 ml of ethyl acetate The extract was further washed twice with 500 ml of water The thus obtained ethyl acetate solution was dried with sodium sulfate concentrated purified by silica gel chromatography