tert-butyl (2S)-2-amino-4-methylpentanoate

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

Procedure: (S)-tert-Butyl 2-amino-4-methylpentanoate (1.0042 g, 5.36 mmol), potassium carbonate (2.446 g, 17.69 mmol), and 1-bromo-2-(2-bromoethoxy)ethane (1.368 g, 5.90 mmol) were combined in acetonitrile (30 mL). The reaction was heated at 80° C. overnight. The reaction was cooled and filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography using 5-50% ethyl acetate/hexanes to give (S)-tert-butyl 4-methyl-2-morpholinopentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.76-3.58 (m, 4H), 3.11 (dd, J=6.9, 8.1, 1H), 2.74-2.53 (m, 4H), 1.71-1.55 (m, 2H), 1.51-1.34 (m, 10H), 0.92 (dd, J=6.6, 7.3, 6H). (S)-tert-Butyl 4-methyl-2-morpholinopentanoate (0.637 g, 2.475 mmol) and 4 N hydrochloric acid in dioxane (5 mL) were combined. The reaction mixture was stirred at ambient temperature for 24 hours, then the solvent removed in vacuo to give (S)-4-methyl-2-morpholinopentanoic acid hydrochloride: MS (DCI+) m/z 202 (M+H)+. The reaction was cooled filtered the solvent removed in vacuo The crude material was purified by silica gel chromatography

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

Procedure: To a solution of 4-phenyl-2-[acetylthio-methyl]butyric acid (3.57 g, 14.2 mmole) in 66 mL of THF at 0° C., was added (S)-leucine, t-butyl ester (2.91 g 15.6 mmole) and 1-hydroxybenzotriazole hydrate (HOBTH2O, 2.86 g, 21.2 mmole) and N-methylmorpholine (4.29 g, 42.4 mmole). The mixture was stirred at 0° C. for 15 minutes, then 5.42 g of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC′HCl, 28.3 mmol) was added and the mixture stirred overnight. The solution was worked up by adding 100 mL methylene chloride and the mixture extracted with 3×50 mL of 5% sodium bicarbonate and washed with 2×50 mL of brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with methylene chloride/ethyl acetate (95/5). The product was separated as diastereomeric (R,S) and (S,S) fractions. The absolute stereochemistry of each fraction was not determined. Higher Rf material=1.78 g; lower Rf material=1.90 g. the mixture stirred overnight the mixture extracted with 3×50 mL of 5% sodium bicarbonate washed with 2×50 mL of brine The organic layer was dried over MgSO4 filtered the solvent removed under reduced pressure The residue was purified by flash chromatography on silica gel eluted with methylene chloride/ethyl acetate (95/5) The product was separated as diastereomeric (R,S) and (S,S) fractions

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product of stage (b) was dissolved in THF (20 ml), cooled to -25° C. and with stirring NMM (1.28 g) and then isobutylchloroformate (1.65 g) successively added. After two minutes, a precooled solution of leucine tert-butyl ester (2.15 g) in DMF (5 ml) was added and the mixture stirred at -15° C. for 2 hr. The temperature was raised to 0° C. and stirring continued for 0.5 hr after the addition of 2 M KHCO3 (14 ml). The product was evaporated in vacuo, the residue suspended in ethyl acetate and succesively washed with 5% citric acid, 10% NaHCO3 and brine, dried (MgSO4) and concentrated to a white solid, m.p. 80°-87° (dec). The structure was confirmed by NMR and the product was used in the next stage without further purification. The temperature was raised to 0° C. stirring continued for 0.5 hr The product was evaporated in vacuo succesively washed with 5% citric acid, 10% NaHCO3 and brine dried (MgSO4) concentrated to a white solid, m.p. 80°-87° (dec) the product was used in the next stage without further purification

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

Procedure: By substituting L-leucine tert-butyl ester for the proline tert-butyl ester in the procedure of Example 13, and then submitting the product to the procedure of Examples 14 and 15, N-[2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-Leucine tert-butyl ester, N-[2-acetylthiomethyl-5-aminopentanoyl]-L-leucine and N-(5-amino-2-mercaptomethylpentanoyl)-L-leucine are obtained. are obtained

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

Procedure: A solution of leucine tert-butyl ester (2.0 g, 8.9 mmol) and acetaldehyde (999 ul, 17.9 mmol) was stirred at room temperature for 5 minutes. Anhydrous sodium sulphate was added and the mixture stirred at room temperature for 18 hours. The solid was removed by filtration and the solvent evaporated in vacuo to afford the title compound as an oil. The solid was removed by filtration the solvent evaporated in vacuo

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

Procedure: Prepared from Intermediate F and L-leucine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.31-7.12 (4H, m), 6.38 (1H, s), 3.24-3.04 (2H, m), 2.90-2.69 (4H, m), 1.76-1.56 (1H, m), 1.45 (9H, s), 1.23 (6H, d, J=7.0 Hz), 0.93 (6H, dd, J=10.9, 6.6 Hz). LC/MS: purity >98%, m/z 511 [M+H]+

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

Procedure: Prepared from Intermediate F and L-leucine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.31-7.12 (4H, m), 6.38 (1H, s), 3.24-3.04 (2H, m), 2.90-2.69 (4H, m), 1.76-1.56 (1H, m), 1.45 (9H, s), 1.23 (6H, d, J=7.0 Hz), 0.93 (6H, dd, J=10.9, 6.6 Hz). LC/MS: purity >98%, m/z 511 [M+H]+

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

Procedure: Prepared from Intermediate D and L-leucine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 6.95 (1H, s), 6.33 (1H, s), 4.17 (2H, m), 3.33 (1H, m), 3.28 (1H, m), 2.95 (2H, t, J=12.6 Hz), 2.65 (2H, m), 1.74 (4H, m), 1.57 (11H, m), 1.44 (4H, m), 1.20 (6H, d, J=9.0 Hz), 0.97 (6H, m). LC/MS: purity 96%, m/z 477 [M+H]+

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

Procedure: Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, L-leucine tert-butyl ester was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of leucine t-butyl ester (10 g) in toluene (100 mL) is added thiophene-2-carboxaldehyde (5.0 mL) and the mixture is heated to 90° C. for 2 hours. The mixture was cooled, washed with water, dried over magnesium sulfate, filtered, and evaporated to an oil (14.5 g). The mixture was cooled washed with water dried over magnesium sulfate filtered evaporated to an oil (14.5 g)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of leucine t-butyl ester (10 g) in toluene (100 mL) is added thiophene-2-carboxaldehyde (5.0 mL) and the mixture is heated to 90° C. for 2 hours. The mixture was cooled, washed with water, dried over magnesium sulfate, filtered, and evaporated to an oil (14.5 g). The mixture was cooled washed with water dried over magnesium sulfate filtered evaporated to an oil (14.5 g)

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

Procedure: (S)-tert-Butyl 2-amino-4-methylpentanoate (1.0042 g, 5.36 mmol), potassium carbonate (2.446 g, 17.69 mmol), and 1-bromo-2-(2-bromoethoxy)ethane (1.368 g, 5.90 mmol) were combined in acetonitrile (30 mL). The reaction was heated at 80° C. overnight. The reaction was cooled and filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography using 5-50% ethyl acetate/hexanes to give (S)-tert-butyl 4-methyl-2-morpholinopentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.76-3.58 (m, 4H), 3.11 (dd, J=6.9, 8.1, 1H), 2.74-2.53 (m, 4H), 1.71-1.55 (m, 2H), 1.51-1.34 (m, 10H), 0.92 (dd, J=6.6, 7.3, 6H). (S)-tert-Butyl 4-methyl-2-morpholinopentanoate (0.637 g, 2.475 mmol) and 4 N hydrochloric acid in dioxane (5 mL) were combined. The reaction mixture was stirred at ambient temperature for 24 hours, then the solvent removed in vacuo to give (S)-4-methyl-2-morpholinopentanoic acid hydrochloride: MS (DCI+) m/z 202 (M+H)+. The reaction was cooled filtered the solvent removed in vacuo The crude material was purified by silica gel chromatography