benzyl (2R)-2-aminopropanoate

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

Procedure: 3-Nitrobenzoyl chloride was reacted with D-alanine benzyl ester, then reduced with tin chloride to produce (R)-2-(3-amino-phenyl)-propionic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 11.96 (1H, br s), 9.46 (1H, br s), 8.57 (1H, br d), 8.16 (1H, s), 7.96 (1H, d), 7.54 (1H, d), 7.40-7.35 (1H, m), 4.41 (1H, m), 2.87 (2H, m), 2.63 (1H, m), 1.94-1.32 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.15; H, 8.33; N, 9.04%. C39H59N5O9.2.0 mols H2O requires: C, 60.21; H, 8.16; N, 9.00%.

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

Procedure: 3-Nitrobenzoyl chloride was reacted with D-alanine benzyl ester, then reduced with tin chloride to produce (R)-2-(3-amino-phenyl)-propionic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 11.96 (1H, br s), 9.46 (1H, br s), 8.57 (1H, br d), 8.16 (1H, s), 7.96 (1H, d), 7.54 (1H, d), 7.40-7.35 (1H, m), 4.41 (1H, m), 2.87 (2H, m), 2.63 (1H, m), 1.94-1.32 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.15; H, 8.33; N, 9.04%. C39H59N5O9.2.0 mols H2O requires: C, 60.21; H, 8.16; N, 9.00%.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 30 ml. of DMF were added 2.73 grams (7.1 mmoles) of Nα -t-butyloxycarbonyl-Nα -methyl-O-benzyl-L-tyrosine (prepared by acidification of 3.6 grams of the product from Part A and extraction into ether). The solution was cooled to 0° C., and 2.26 grams (7.1 mmoles) of the tosylate salt of D-alanine, benzyl ester, were added followed by 0.794 grams (7.1 mmoles) of triethylenediamine. The mixture was stirred at 0° C. for five minutes, and 0.96 grams of HBT and 1.46 grams (7.1 mmoles) of DCC were added. The mixture was stirred at 0° C. for two hours and then at room temperature for 24 hours. The mixture then was cooled to 0° C. and filtered. The filtrate was concentrated in vacuo to an oil, and then the oil was dissolved in ethyl acetate and extracted successively with 1 N aqueous sodium bicarbonate, water, 1.5 N citric acid, and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to an oil. The oil was dissolved in 60 ml. of ethanol, and 1.5 grams of 5% palladium on carbon were added to the mixture as a water slurry. Nitrogen was bubbled into the reaction mixture through a gas dispersion tube for five minutes followed by hydrogen gas for 24 hours. The mixture was flushed with nitrogen, and the catalyst was removed by filtration. The reaction mixture was concentrated in vacuo to an amorphous solid to give 2.5 grams (99 percent) of the title compound. The mixture was stirred at 0° C. for two hours at room temperature for 24 hours The mixture then was cooled to 0° C. filtered The filtrate was concentrated in vacuo to an oil the oil was dissolved in ethyl acetate extracted successively with 1 N aqueous sodium bicarbonate, water, 1.5 N citric acid, and water The organic phase was dried over magnesium sulfate concentrated in vacuo to an oil The oil was dissolved in 60 ml of ethanol, and 1.5 grams of 5% palladium on carbon were added to the mixture as a water slurry Nitrogen was bubbled into the reaction mixture through a gas dispersion tube for five minutes followed by hydrogen gas for 24 hours The mixture was flushed with nitrogen the catalyst was removed by filtration The reaction mixture was concentrated in vacuo to an amorphous solid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 30 ml. of DMF were added 2.73 grams (7.1 mmoles) of Nα -t-butyloxycarbonyl-Nα -methyl-O-benzyl-L-tyrosine (prepared by acidification of 3.6 grams of the product from Part A and extraction into ether). The solution was cooled to 0° C., and 2.26 grams (7.1 mmoles) of the tosylate salt of D-alanine, benzyl ester, were added followed by 0.794 grams (7.1 mmoles) of triethylenediamine. The mixture was stirred at 0° C. for five minutes, and 0.96 grams of HBT and 1.46 grams (7.1 mmoles) of DCC were added. The mixture was stirred at 0° C. for two hours and then at room temperature for 24 hours. The mixture then was cooled to 0° C. and filtered. The filtrate was concentrated in vacuo to an oil, and then the oil was dissolved in ethyl acetate and extracted successively with 1 N aqueous sodium bicarbonate, water, 1.5 N citric acid, and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to an oil. The oil was dissolved in 60 ml. of ethanol, and 1.5 grams of 5% palladium on carbon were added to the mixture as a water slurry. Nitrogen was bubbled into the reaction mixture through a gas dispersion tube for five minutes followed by hydrogen gas for 24 hours. The mixture was flushed with nitrogen, and the catalyst was removed by filtration. The reaction mixture was concentrated in vacuo to an amorphous solid to give 2.5 grams (99 percent) of the title compound. The mixture was stirred at 0° C. for two hours at room temperature for 24 hours The mixture then was cooled to 0° C. filtered The filtrate was concentrated in vacuo to an oil the oil was dissolved in ethyl acetate extracted successively with 1 N aqueous sodium bicarbonate, water, 1.5 N citric acid, and water The organic phase was dried over magnesium sulfate concentrated in vacuo to an oil The oil was dissolved in 60 ml of ethanol, and 1.5 grams of 5% palladium on carbon were added to the mixture as a water slurry Nitrogen was bubbled into the reaction mixture through a gas dispersion tube for five minutes followed by hydrogen gas for 24 hours The mixture was flushed with nitrogen the catalyst was removed by filtration The reaction mixture was concentrated in vacuo to an amorphous solid

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

Procedure: 3-Nitrobenzoyl chloride was reacted with D-alanine benzyl ester, then reduced with tin chloride to produce (R)-2-(3-amino-phenyl)-propionic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 11.96 (1H, br s), 9.46 (1H, br s), 8.57 (1H, br d), 8.16 (1H, s), 7.96 (1H, d), 7.54 (1H, d), 7.40-7.35 (1H, m), 4.41 (1H, m), 2.87 (2H, m), 2.63 (1H, m), 1.94-1.32 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.15; H, 8.33; N, 9.04%. C39H59N5O9.2.0 mols H2O requires: C, 60.21; H, 8.16; N, 9.00%.