Development of Scalable Synthesis of 5-Butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a Dual Inhibitor of Nitric Oxide and Prostaglandin E2 Production

0533528 - ÚOCHB 2021 RIV US eng J - Journal Article
Dosoudil, P. - Kotek, V. - Kolman, Viktor - Baszczyňski, Ondřej - Kaiser, Martin Maxmilian - Janeba, Zlatko - Havránek, M.
Development of Scalable Synthesis of 5-Butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a Dual Inhibitor of Nitric Oxide and Prostaglandin E2 Production.
Organic Process Research & Development. Roč. 24, č. 9 (2020), s. 1718-1724. ISSN 1083-6160. E-ISSN 1520-586X
R&D Projects: GA TA ČR(CZ) TE01020028
Institutional support: RVO:61388963
Keywords : pyrimidines * Eaton’s reagent * upscale * C-acylation
OECD category: Organic chemistry
Impact factor: 3.317, year: 2020
Method of publishing: Limited access
https://doi.org/10.1021/acs.oprd.0c00324

We report a scalable efficient synthesis of 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a dual inhibitor of nitric oxide and prostaglandin E2 production with potent anti-inflammatory properties. The original five-step synthesis (40% overall yield) was based on two Suzuki–Miyaura reactions and required chromatographic purification of both the intermediate and final products. The novel synthetic pathway is based on cyclization of 2-butyl-1-(4-methoxyphenyl)-3-phenylpropane-1,3-dione with guanidinium methanesulfonate using Eaton’s reagent (P2O5/MsOH) at 50 °C. The two-step synthesis (34% overall yield) can be performed on a multigram to kilogram scale, and purification of the final product consists of simple extraction (dichloromethane) and crystallization (ethyl acetate and methanol).
Permanent Link: http://hdl.handle.net/11104/0312366