Construction of N-Boc-2-Alkylaminoquinazolin-4(3 H)-Ones via a Three-Component, One-Pot Protocol Mediated by Copper(II) Chloride that Spares Enantiomeric Purity

Abstract

Chiral 2-alkylquinazolinones are key synthetic intermediates, but their preparation in high optical purity is challenging. Thus, a multicomponent procedure integrating anthranilic acids, N-Boc-amino acids, and amines in the presence of methanesulfonyl chloride, N-methylimidazole, and copper(II) chloride was developed to mildly afford N-Boc-2-alkylaminoquinazolin-4(3H)-ones with excellent preservation of enantiomeric purity (>99% ee). Copper(II) chloride was essential to retaining enantiopurity, and reaction component structural changes were well tolerated, resulting in an efficient, all-in-one procedure that promotes sequential coupling, lactonization, aminolysis, and cyclization in good yields. The method was applied to the rapid assembly of four key intermediates used in the synthesis of high profile quinazolinones, including several PI3K inhibitor drugs.

Keywords: PI3 kinase; copper-mediated; enantiopurity; quinazolinone; racemization.

Figure 1

Selected 2‐alkylaminoquinazolin‐4(3H)‐ones.

Scheme 1

General synthetic approaches to N‐Boc‐quinazolinones.

Scheme 2

Exploratory chemistry leading to 12 a formation.

Scheme 3

Formal syntheses of acalisib 3, ispinesib 4 and quinazolinone 5 using the one‐pot procedure on a 1.0 mmol scale (0.07 M). Yields reflect isolated product and %ee was determined by chiral HPLC comparison of peak AUCs.

Scheme 4

Control experiments revealing need for CuCl₂.

Scheme 5

Proposed role of CuCl₂ in attenuating racemization.