Practical Synthesis of 3-Carboxy-(2R)- [[hydroxy[(tetradecyl)oxy]phosphinyl]oxy]-N,N,N-trimethyl-1-propanaminium Hydroxide Inner Salt (CPI975): A Carnitine Palmitoyltransferase I Inhibitor

Abstract

An efficient, safe, and cost-effective synthesis of 3-carboxy-(2R)-[[hydroxy[(tetradecyl)oxy]phosphinyl]oxy]-N,N,N-trimethyl-1-propanaminium hydroxide inner salt (1, CPI975), a carnitine palmitoyltransferase I inhibitor, is described. The reaction of 1-tetradecanol (2) with stoichiometric amounts of PCl3 in THF at −15 to −20 °C furnished 1-tetradecyl phosphorochloridate (3). Treatment of 3 directly with l-carnitine (7) in THF in the presence of 2,4,6-collidine afforded 8, which was oxidized with bromine to afford a crude aqueous solution of 1. Desalting was done using a cheap, stable, and recyclable resin Amberlite XAD-4. The drug substance was purified by recrystallization from a mixture of ethanol and THF. The yield of 1 was 65% with 99.7% purity. Alternatively, instead of desalting with Amberlite XAD-4 resin, 1 can be isolated by an extraction with 1-decanol, followed by precipitation with acetone and recrystallization from ethanol and THF mixture.