A practical synthesis for (S)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione and its application in the synthesis of a novel liver X receptor β-selective agonist

In this manuscript, the chiral separation of novel liver X receptor (LXR) β-selective agonist (±)-1 revealed that (S)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (+)-2 was the essential moiety (tail) to express LXR β-selective agonistic activity in a head-to-tail molecular design. The requisite configuration of (+)-2 was determined as the (S)-form by X-ray crystal structure analysis of (+)-halogenated 4. We obtained (S)-methyl 2-amino-2-(4-(1-methylethoxy)phenyl)propionate (+)-7 by resolution with l-mandelic acid and established a practical synthesis for (+)-2.

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(S)-3-(4-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-2,6-di-n-propylphenoxy)butyl)-5-(4-(1-methylethoxy)-phenyl)-5-methylimidazolidine-2,4-dioneC32H40F6N2O5ee = 99%[α]D20 = +32.2 (c 1.00, MeOH)Absolute configuration: (S)

(S)-5-(4-(1-Methylethoxy)phenyl)-5-methylimidazolidine-2,4-dioneC13H16N2O3ee = 99%[α]D20 = +89.7 (c 1.0, MeOH)Absolute configuration: (S)Source of chirality: l-(+)-mandelic acid

(S)-5-(3-Chloro-4-(1-methylethoxy)phenyl)-5-methyl-imidazolidine-2,4-dioneC13H15ClN2O3[α]D20 = +81.4 (c 1.0, MeOH)Absolute configuration: (S)

(S)-5-(3-Bromo-4-(1-methylethoxy)phenyl)-5-methyl-imidazolidine-2,4-dioneC13H15BrN2O3[α]D20 = +79.7 (c 0.98, MeOH)Absolute configuration: (S)

Hydrochloric acid of (S)-methyl 2-amino-2-(4-(1-methylethoxy)phenyl)-propanoateC13H20ClNO3ee = 99%[α]D20 = +79.8 (c 1.0, MeOH)Absolute configuration: (S)Source of chirality: l-(+)-mandelic acid