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■ Amidation of Hyaluronic Acid with a Methotrexate-Derived Amine: Optimization of the Key Reaction for the Synthesis of a Candidate Drug for the Trearment of Osteoarthritis

Akie Homma,* Takenori Ishizawa, Haruhiko Sato,* Akira Okamachi, Takashi Emura, Tatsuya Kato, Tetsu Matsuura, Shigeo Sato, Masahisa Ikemi, Hironoshin Kitagawa, Tadashi Morikawa, Hitoshi Ikeya, and Koichi Takahashi

*API Process Department, Chugai Pharmaceutical Company, Ltd., 5-5-1, Ukima, Kita-ku, Tokyo 115-0051, Japan

Abstract

Optimal amidation conditions between hyaluronic acid (HA) and a methotrexate (MTX)-derived amine that gave rise to a HA-MTX conjugate having a molecular weight of ~2000 kDa have been established based on a model experiment using a tryptophan-derived amine in aqueous THF. This method is robust and provides a conjugate with properties of primary importance for efficacy—MW and amine binding ratio—that satisfy the criteria for a HA-MTX conjugate to be a good candidate.