Preparation of [2′,3′,5′,6′-2H4]pteroylglutamic acid

Abstract

Folic acid plays a key role in nucleic acid biosynthesis, essential for normal cell proliferation and function. Localized folate deficiencies may be related to changes in cytology associated with cancer development; analogs of folic acid, such as methotrexate, are potent chemotherapeutic agents and are widely used either alone or in combination therapy for many types of cancer. In this report we describe the synthesis of a tetra-deuterated folic acid from perdeuterated toluene. The primary intermediate, N-(4-amino [2,3,5,6-²H₄]benzoyl)-L-glutamic acid diethyl ester was coupled to N(2′)-acetyl-6-formylpterin to create [2′,3′,5′,6′-²H₄]folic acid. A similar scheme can be used for the preparation of [1′,2′,3′,4′,5′,6′-¹³C₆]folic acid from [¹³C₆] ring labeled toluene.