A novel strategy for the manufacture of idelalisib: controlling the formation of an enantiomer

Abstract

A novel and scalable synthesis of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone, idelalisib 1, has been developed.

Synthesis and evaluation of anticancer, antiphospholipases, antiproteases, and antimetabolic syndrome activities of some 3H-quinazolin-4-one derivatives

“…In addition to this, many marketed drugs or experimental drug candidates incorporate this pharmacophore as part of the overall topography of the molecules 16 such as ispinesib, nolatrexed, and raltitrexed (the anticancer agents); afloqualone with sedative and muscle relaxant effects, balaglitazone with antidiabetic activities, proquazone (as non-steroidal anti-inflammatory agent), and elinogrel (as reversible P2Y12 receptor antagonist) which is used for the treatment of acute coronary syndrome. Moreover, several new methodologies have been developed for the synthesis of 4-quinazolinone derivatives either using one pot multicomponent approaches 17 or via multistep routes for investigating their pharmacological potential as dual EGFR/HER2 inhibitors 18 , phosphoinositide 3-kinase inhibitors 19 , and as antihypertensive 20 , antioxidant 21 , anticonvulsant 22 , and anti-inflammatory 23 agents.…”

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

“… [4b–d,5,9] Alternatively, isobutyl chloroformate and N ‐methylmorpholine (NMM) have been used in place of the phosphite reagents to construct the quinazolinone core, [8,10] while other methods generate anthranilamides via peptide coupling, followed by cyclization using HMDS/I 2 , [11] TMSCl, [12] or bis(trimethylsilyl)acet‐amide [13] . Preparing anthranil‐amides from 2‐nitrobenzoic acids has also been explored [13–14] as a means to afford Boc‐protected 2‐alkylaminoquinazolin‐4(3 H )‐ones 7 with high enantiopurity via Mumm rearrangement, followed by reduction and cyclization [15] . Nonetheless, many of these methods demonstrated one or more limitations such as low overall yield, multistage purification, narrow substrate scope, need for synthetically challenging starting materials, use of sensitizing coupling reagents, [16] or erosion of enantiopurity.…”

“…To assess if the protocol was beneficial in the synthesis of previously reported N ‐Boc‐2‐alkylamino‐quinazolinones, we approached the formal syntheses of four quinazolinone drugs or candidates for which the requisite N ‐Boc‐quinazolinones were known. Quinazolinone 12 p , a key idelalisib 1 synthetic intermediate, [3a,14–15] had been reportedly prepared via a phosphite‐mediated strategy, though the yield and enantiopurity was not reported (Table 3, entry 1).…”

Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3H)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease

“…Benzoic acid 33 was reacted with different amines under standard 1-[bis­(dimethylamino)­methylene]-1 H -1,2,3-triazolo­[4,5- b ]­pyridinium 3-oxid hexafluorophosphate (HATU)-mediated coupling condition to yield the amides 34a – g , followed by treatment with acyl chloride to afford the diamides 35a – g . Hexamethyldisilazane (HMDS)/ZnCl 2 -mediated cyclization of 35a – g in acetonitrile provided the quinazolinone analogues 36a – g , which were then converted to the target compounds 6 – 7 , 9 , and 14 – 17 by nucleophilic substitution as racemic mixtures.…”