Method of Synthesizing 2-Amino-6-((1R,2S)-1,2-dihydroxypropyl)pteridin 4(1H)-one and (6R)-L-Erythro-tetrahydrobiopterin

Abstract

The present disclosure provides a method that efficiently produces (6R)-tetrahydrobiopterin in high yield and purity. The method includes the step of hydrolyzing diacetylbiopterin to biopterin under basic conditions in a biphasic mixture comprising an organic phase and an aqueous phase. After substantially complete hydrolysis of diacetyl¬biopterin, the aqueous phase containing biopterin can be separated from the organic phase containing most of the organic impurities, which avoids the time-consuming step of isolating biopterin as a solid. The aqueous solution containing biopterin is stereoselectively hydrogenated to (6R)-tetrahydrobiopterin under basic conditions and high hydrogen pressure in the presence of a metal catalyst (e.g., a platinum catalyst). To improve the purification of an acid addition salt of (6R)-tetrahydrobiopterin (e.g., (6R)-tetrahydrobiopterin dihydrochloride), any residual salts (e.g., sodium salts) in the aqueous solution after the hydrogenation reaction can be removed by contacting the aqueous solution with an ion (e.g., cation) exchange resin or column. Alternatively, removal of residual salts from the aqueous solution can be omitted if an organic amine (e.g., diethyl- amine or triethylamine) rather than an inorganic base is used in the hydrolysis and / or hydrogenation reactions.