The Development of a Dimroth Rearrangement Route to AZD8931

Abstract

Recently, the aminoquinazoline motif has been highly prevalent in anticancer pharmaceutical compounds. Synthetic methods are required to make this structure on a multikilo scale and in high purity. The initial route to aminoquinazoline AZD8931 suffered from the formation of late-stage impurities. To avoid these impurities, a new high-yielding Dimroth rearrangement approach to the aminoquinazoline core of AZD8931 was developed. Assessment of route options on a gram scale demonstrated that the Dimroth rearrangement is a viable approach. The processes were then evolved for large-scale production with learning from a kilo campaign and two plant-scale manufactures. Identification of key process impurities offers an insight into the mechanisms of the Dimroth rearrangement as well as the hydrogenation of a key intermediate. The final processes were operated on a 30 kg scale delivering the target AZD8931 in 41% overall yield.

A short review on synthetic strategies towards quinazoline based anticancer drugs

“…Compared to gefitinib or erbB2 inhibitors, AZD8931 was a much more potent inhibitor of EGF-driven cellular proliferation in multiple tumour cell lines 46 William et al reported an industrial scale synthesis using Dimroth rearrangement route as has been shown to be utilized to some of commercially available drug of this series. 47 All in all, Dimroth Rearrangement is the most versatile method to synthesize amino quinazoline derivatives. A general synthetic approach for isolation of such compounds is depicted in Scheme 18.…”

Development of a Mild and Efficient Process for Ir-Catalyzed N-Alkylation of 4-Bromopyridin-2-amine with a Primary Alcohol via Borrowing Hydrogen

“…This reaction typically proceeds by conversion of an alcohol to a carbonyl functionality via transition-metal-catalyzed oxidative dehydrogenation followed by condensation with an amine to form an imine intermediate and subsequent reduction of the imine with metal-hydride to form an N -alkylated product. Since the pioneering work by Watanabe et al and Grigg et al, several reports have been published for N -alkylation of amines with primary alcohols using Co, Fe, Ir, Mn, Ni, and Ru catalysts. Most of these reaction conditions are characterized by the use of specialized ligands ( N -heterocyclic carbene, pincer, etc.…”

Manufacturable Process of a Novel EGFR Inhibitor (Larotinib) for the Treatment of ESCC

“…In addition, some unexpected nitro impurities are easily generated in the nitration reaction, such as nitro regioisomers 18 and 19 and dinitro 20 , as shown in Figure . For the nitroreduction, the exothermic system and side reactions require strict control so as to prevent potential safety hazards, in which intermediates (nitroso 21 , hydroxylamine 22 ), in particular, hydroxylamine 22 , are prone to have side reactions and generate impurities such as amide 23 , azoxy 24 , azo 25 , and hydrazo 26 , , as shown in Figure . In addition, route III requires high-quality equipment so as to tolerate the high reaction temperature (130 °C).…”