4-Methylmorpholine → Methyl 3-cyclohexyl-D-alaninate--hydrogen chloride (1/1)

Participants

Reaction Steps

(2R)-2-Amino-3-cyclohexylpropanoic acid methyl ester hydrochloride was prepared from Boc-(2R)-2-Amino-3-cyclohexylpropanoic acid (30 g, 0.11 mole) in 500 mL of methanol and 250 mL of 4N hydrochloric acid in dioxane for overnight at room temperature in 93% yield. This (22.58 g, 0.101 mole) was coupled with Boc-Proline (25.89 g, 0.11 mole) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (21.31 g, 0.11 mole), 1-hydroxybenzotriazole monohydride (HOBT) (15.0 g, 0.11 mole) and N-methylmorpholine (NMM) (12.2 mL, 0.11 mole) (EDC and HOBT method) in methylene chloride. The reaction was carried out at room temperature for overnight. Ethyl acetate was added and the organic layer was washed with saturated sodium bicarbonate, brine, 0.2M phosphoric acid, brine and dried over sodium sulfate. Evaporation of the solvent gave 35.03 g of dipeptide in 91% yield (MS: (M+H)+ =383). This was followed by deprotection of Boc-group, then coupling with N-alpha-Cbz-N-epsilon-Boc-Lysine to yield N-alpha-Cbz-Lysyl(N-epsilon-Boc)-Prolyl-{(2R)-2-Amino-3-cyclohexylpropanoyl}-OMe (MS: (M+H)+ =645) in 89% yield using the conditions mentioned above (EDC and HOBT method).

Provenance & Evidence