Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Direct N1-Selective Alkylation of Hydantoins Using Potassium Bases
Yumi ShintaniKoichi KatoMasashi KawamiMikihisa TakanoTakuya Kumamoto
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Supplementary material

2021 Volume 69 Issue 4 Pages 407-410

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Abstract

Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N3 can be more easily alkylated than N1 under basic conditions. In this study, we explored methods for direct N1-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide (tBuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N1-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.

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