Methods for producing N-(8-[2-hydroxybenzoyl]-amino) caprylic acid
View Patent ↗Disclosed are improved methods for the synthesis of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid. Certain compounds have been found useful for preventing the formation of a colored impurity when included in an ester hydrolysis reaction. Conducting ester hydrolysis in anaerobic conditions has also been found to minimize the formation of the color impurity. Also disclosed are improved methods for synthesizing the sodium salt of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid.
1. A method for synthesizing N-(8-[2-hydroxybenzoyl]-amino) caprylic acid comprising the step of:
hydrolyzing 2,4-dioxo-1,3-benzoxazinyloctanoic acid ethyl ester by admixing 2,4-dioxo-1,3-benzoxazinyloctanoic acid ethyl ester with sodium hydroxide, water, and a member selected from the group consisting of ethylenediamine tetraacetic acid, ascorbic acid, NaHSO3, and triphenylphosphine.
2. The method of claim 1 , further comprising the step of admixing acetone and hydrochloric acid after said hydrolyzing step.
3. A method for synthesizing N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt, comprising:
admixing N-(8-[2-hydroxybenzoyl]-amino) caprylic acid suspended in 2-propanol with aqueous sodium hydroxide to form a solution of N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt: and
adding additional 2-propanol to said solution, seeding said solution of N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt with crystalline N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt to cause said N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt to precipitate out of said solution, and then adding more 2-propanol to said solution.
4. The method of claim 3 wherein said crystalline N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt is anhydrous N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt.