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

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• 作者：Mahavir Prashad ; John C. Amedio ; Lech Ciszewski ; George Lee ; Carmine Villa ; Kau-Ming Chen ; Kapa Prasad ; and Oljan Repi<img src="http ; //pubs.acs.org/images/entities/ccaron.gif" border="0">
• 刊名：Organic Process Research & Development
• 出版年：2002
• 出版时间：November 2002
• 年：2002
• 卷：6
• 期：6
• 页码：773 - 776
• 全文大小：46K
• 年卷期：v.6,no.6(November 2002)
• ISSN：1520-586X

文摘

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 carnitinepalmitoyltransferase I inhibitor, is described. The reaction of1-tetradecanol (2) with stoichiometric amounts of PCl₃ in THFat -15 to -20 <IMG SRC="/images/entities/deg.gif">C furnished 1-tetradecyl phosphorochloridate(3). Treatment of 3 directly with L-carnitine (7) in THF in thepresence of 2,4,6-collidine afforded 8, which was oxidized withbromine to afford a crude aqueous solution of 1. Desalting wasdone using a cheap, stable, and recyclable resin Amberlite XAD-4. The drug substance was purified by recrystallization from amixture of ethanol and THF. The yield of 1 was 65% with99.7% purity. Alternatively, instead of desalting with AmberliteXAD-4 resin, 1 can be isolated by an extraction with 1-decanol,followed by precipitation with acetone and recrystallizationfrom ethanol and THF mixture.