Crystalline amino-protected amino acids and method of preparation

A method for preparing crystalline alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine which comprises the steps of

• providing a solution of alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine in a substantially water-immiscible polar solvent therefor;
• reducing the solubility of the alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine in said solution while maintaining the water content of the resulting mother liquor at no more than about 0.9 weight percent, in the presence of a nucleating agent, until the mother liquor becomes supersaturated with respect to the alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine present and a solid crystalline phase separates out from said mother liquor;
• and
• harvesting the separated solid crystalline phase.

A method for preparing crystalline alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine which comprises the steps of

• providing a water-containing solution of alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine in a substantially water-immiscible polar solvent therefor;
• admixing said solution with a non-polar organic liquid phase modifier that is miscible with said water-immiscible solvent but is not a solvent for the alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine, said phase modifier being admixed in an amount sufficient to reduce the solubility of the alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine in the solution so that the solution becomes supersaturated at about ambient temperature;
• refluxing the resulting liquid admixture at a temperature in the range of about 70.degree. C. to about 90.degree. C. until the water content of the liquid admixture is no more than about 0.9 weight percent;
• thereafter cooling the refluxed liquid admixture to a temperature below the saturation point for the L-lysine present;
• adding an effective amount of nucleating agent to the cooling refluxed liquid admixture when the temperature thereof is no more than about ambient temperature;
• and
• harvesting crystalline alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl L-lysine from the cooled and nucleated liquid admixture.

A method for preparing crystalline alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl-L-lysine which comprises the steps of

• preparing a water-containing solution of an addition salt of alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl-L-lysine;
• admixing said solution with a water-immiscible polar solvent for alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl-L-lysine in free acid form;
• acidifying the resulting admixture to convert the dissolved addition salt of alpha-tert-butyloxycarbonyl-epsilon-benzyloxycarbonyl-L-lysine to the free acid form thereof;
• agitating the acidified admixture to extract the free acid form into the polar solvent;
• concentrating the extract by distillation at a temperature of about 70.degree. C. to about 90.degree. C. until the concentration of the free acid form in the polar solvent is adjusted to about 40 weight percent, based on the volume of the solvent;
• cooling the concentrated extract to a temperature of about 50.degree. C.;
• reducing the solubility of the free acid form in the cooled extract by admixing said extract with a non-polar organic liquid phase modifier that is miscible with said polar solvent but is not a solvent for the alpha-butyloxycarbonyl-epsilon-benzylcarbonyl-L-lysine, said phase modifier being added in an amount sufficient to reduce the solubility of the free acid form in the resulting admixture so that the admixture becomes supersaturated at about ambient temperature;
• refluxing the resulting liquid admixture at a temperature in the range of about 80.degree. C. to about 90.degree. C. until the water content of the liquid admixture is no more than about 0.9 weight percent, based on the volume of the liquid admixture;
• thereafter cooling the refluxed liquid admixture to a temperature in the range of about 0.degree. C. to about 5.degree. C.;
• adding an effective amount of nucleating agent to the cooling refluxed liquid admixture when the temperature thereof is no more than about 10.degree. C.;
• reducing the solubility of the free acid form in the cooled admixture having the reduced water content, in the presence of the nucleating agent, until a solid crystalline material is formed;
• and
• harvesting the formed solid crystalline material.