1,5,5-trimethylimidazolidine-2,4-dione

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A suspension of 21.3 g of 1,5,5-trimethylhydantoin, 5.86 g of paraformaldehyde and 34 ml of hydrogen bromide in acetic acid (33%) was heated to 80° for 2 hrs., again treated with 7.9 ml of hydrogen bromide in acetic acid and heated for a further 2.5 hrs. The solution was cooled to 0°, diluted with 100 ml of methylene chloride and subsequently treated at 0° with 100 ml of ice-cold water. The methylene chloride phase was washed with water, dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 30.9 g (88%) of pure 3-bromomethyl-1,5,5-trimethylhydantoin, m.p. 86-88°. IR (KBr): 1780s and 1732s (C=O). was heated to 80° for 2 hrs heated for a further 2.5 hrs The solution was cooled to 0° The methylene chloride phase was washed with water dried concentrated The residue was crystallized from t-butyl methyl ether/hexane the crystallizate was dried

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

Procedure: 203 ml 1.6M Butyllithium in hexane were added to a solution of 46.0 ml diisopropylamine in 120 ml THF at 0° over 1 h. The resultant LDA-solution was stirred at 0° for 1 h and then cooled down to −75°. 50.8 g 3-cyclopentyl-propionic acid methylester dissolved in 65 ml THF were added at −75° over 1 h and stirring at that temperature was continued for 1 h. 67.6 g 3-(3-tert-butoxy-2-oxo-propyl)-1,5,5-trimethyl-imidazolidine-2,4-dione dissolved in 65 ml THF were added at −75° over 1 h and after additional stirring at −75° for 1 h, 50 ml conc. H2SO4 were added over 15 minutes. The reaction mixture was refluxed for 3 h, cooled down to r.t. and hydrolyzed with 300 ml deionized water. The organic layer was separated, washed with 10% brine and dried over Na2SO4. Filtration and evaporation of the solvent afforded 96.5 g crude 3-(4-cyclopentylmethyl-3-hydroxy-5-oxo-tetrahydro-furan-3-ylmethyl)-(1,5,5-trimethyl-imidazolidine-2,4-dione as a yellow oil, which was used without purification for the next step. 3-Cyclopentyl-propionic acid methylester was prepared from the corresponding acid (ACROS No. 11161). The methylester is also available at Chemische Fabrik K. Bucher. cooled down to −75° were added at −75° over 1 h were added at −75° over 1 h after additional stirring at −75° for 1 h The reaction mixture was refluxed for 3 h The organic layer was separated washed with 10% brine dried over Na2SO4 Filtration and evaporation of the solvent

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

Procedure: 1,5,5-Trimethylimidazolidine-2,4-dione (100 mg, 0.70 mmol) and 1-isocyanatohexane (107.4 mg, 0.84 mmol) were reacted in analogy to example 1. Yield: 31.5 mg (17%), M+H+: 270.17.

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

Procedure: To a solution of the title F compound, (2R)-[t-butyloxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]-4-iodobutyric acid t-butyl ester (0.6 g, 0.94 mmol) in 10 mL DMF is added 3,4,4-trimethyl-2,5-dioxoimidazoline and potassium carbonate (0.65 g, 4.72 mmol) followed by 2 mg of 18-crown-6. The reaction mixture is stirred at room RT for 3 h, then partitioned between water and EtOAc. The organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 1/19—EtOAc/hexane) affords the title compound as a white foam (0.25 g, 41%). partitioned between water and EtOAc The organic solution is washed with brine dried over anhydrous Na2SO4 concentrated

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

Procedure: 203 ml 1.6M Butyllithium in hexane were added to a solution of 46.0 ml diisopropylamine in 120 ml THF at 0° over 1 h. The resultant LDA-solution was stirred at 0° for 1 h and then cooled down to −75°. 50.8 g 3-cyclopentyl-propionic acid methylester dissolved in 65 ml THF were added at −75° over 1 h and stirring at that temperature was continued for 1 h. 67.6 g 3-(3-tert-butoxy-2-oxo-propyl)-1,5,5-trimethyl-imidazolidine-2,4-dione dissolved in 65 ml THF were added at −75° over 1 h and after additional stirring at −75° for 1 h, 50 ml conc. H2SO4 were added over 15 minutes. The reaction mixture was refluxed for 3 h, cooled down to r.t. and hydrolyzed with 300 ml deionized water. The organic layer was separated, washed with 10% brine and dried over Na2SO4. Filtration and evaporation of the solvent afforded 96.5 g crude 3-(4-cyclopentylmethyl-3-hydroxy-5-oxo-tetrahydro-furan-3-ylmethyl)-(1,5,5-trimethyl-imidazolidine-2,4-dione as a yellow oil, which was used without purification for the next step. 3-Cyclopentyl-propionic acid methylester was prepared from the corresponding acid (ACROS No. 11161). The methylester is also available at Chemische Fabrik K. Bucher. cooled down to −75° were added at −75° over 1 h were added at −75° over 1 h after additional stirring at −75° for 1 h The reaction mixture was refluxed for 3 h The organic layer was separated washed with 10% brine dried over Na2SO4 Filtration and evaporation of the solvent

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

Procedure: 203 ml 1.6M Butyllithium in hexane were added to a solution of 46.0 ml diisopropylamine in 120 ml THF at 0° over 1 h. The resultant LDA-solution was stirred at 0° for 1 h and then cooled down to −75°. 50.8 g 3-cyclopentyl-propionic acid methylester dissolved in 65 ml THF were added at −75° over 1 h and stirring at that temperature was continued for 1 h. 67.6 g 3-(3-tert-butoxy-2-oxo-propyl)-1,5,5-trimethyl-imidazolidine-2,4-dione dissolved in 65 ml THF were added at −75° over 1 h and after additional stirring at −75° for 1 h, 50 ml conc. H2SO4 were added over 15 minutes. The reaction mixture was refluxed for 3 h, cooled down to r.t. and hydrolyzed with 300 ml deionized water. The organic layer was separated, washed with 10% brine and dried over Na2SO4. Filtration and evaporation of the solvent afforded 96.5 g crude 3-(4-cyclopentylmethyl-3-hydroxy-5-oxo-tetrahydro-furan-3-ylmethyl)-(1,5,5-trimethyl-imidazolidine-2,4-dione as a yellow oil, which was used without purification for the next step. 3-Cyclopentyl-propionic acid methylester was prepared from the corresponding acid (ACROS No. 11161). The methylester is also available at Chemische Fabrik K. Bucher. cooled down to −75° were added at −75° over 1 h were added at −75° over 1 h after additional stirring at −75° for 1 h The reaction mixture was refluxed for 3 h The organic layer was separated washed with 10% brine dried over Na2SO4 Filtration and evaporation of the solvent

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

Procedure: A suspension of 21.3 g of 1,5,5-trimethylhydantoin, 5.86 g of paraformaldehyde and 34 ml of hydrogen bromide in acetic acid (33%) was heated to 800 for 2 hrs., again treated with 7.9 ml of hydrogen bromide in acetic acid and heated for a further 2.5 hrs. The solution was cooled to 0°, diluted with 100 ml of methylene chloride and subsequently treated at 0° with 100 ml of ice-cold water. The methylene chloride phase was washed with water, dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 30.9 g (88%) of pure 3-bromomethyl-1,5,5-trimethylhydantoin, m.p. 86-88°. IR (KBr): 1780s and 1732s (C═O). was heated to 800 for 2 hrs heated for a further 2.5 hrs The solution was cooled to 0° The methylene chloride phase was washed with water dried concentrated The residue was crystallized from t-butyl methyl ether/hexane the crystallizate was dried

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

Procedure: A suspension of 21.3 g of 1,5,5-trimethylhydantoin, 5.86 g of paraformaldehyde and 34 ml of hydrogen bromide in acetic acid (33%) was heated to 80° for 2 hrs., again treated with 7.9 ml of hydrogen bromide in acetic acid and heated for a further 2.5 hrs. The solution was cooled to 0°, diluted with 100 ml of methylene chloride and subsequently treated at 0° with 100 ml of ice-cold water. The methylene chloride phase was washed with water, dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 30.9 g (88%) of pure 3-bromomethyl-1,5,5-trimethylhydantoin, m.p. 86-88°. IR (KBr): 1780s and 1732s (C=O). was heated to 80° for 2 hrs heated for a further 2.5 hrs The solution was cooled to 0° The methylene chloride phase was washed with water dried concentrated The residue was crystallized from t-butyl methyl ether/hexane the crystallizate was dried

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

Procedure: A suspension of 21.3 g of 1,5,5-trimethylhydantoin, 5.86 g of paraformaldehyde and 34 ml of hydrogen bromide in acetic acid (33%) was heated to 80° for 2 hrs., again treated with 7.9 ml of hydrogen bromide in acetic acid and heated for a further 2.5 hrs. The solution was cooled to 0°, diluted with 100 ml of methylene chloride and subsequently treated at 0° with 100 ml of ice-cold water. The methylene chloride phase was washed with water, dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 30.9 g (88%) of pure 3-bromomethyl-1,5,5-trimethylhydantoin, m.p. 86-88°. IR (KBr): 1780s and 1732s (C=O). was heated to 80° for 2 hrs heated for a further 2.5 hrs The solution was cooled to 0° The methylene chloride phase was washed with water dried concentrated The residue was crystallized from t-butyl methyl ether/hexane the crystallizate was dried

Conditions: temp:0.00; pressure:0.00; stir: