Organic Process Research & Development 2003, 7, 733−742
A Practical Synthesis of 6-[2-(2,5-Dimethoxyphenyl)ethyl]-4-ethylquinazoline and the Art of Removing Palladium from the Products of Pd-Catalyzed Reactions Kurt Ko¨nigsberger, Guang-Pei Chen, Raeann R. Wu, Michael J. Girgis, Kapa Prasad,* Oljan Repicˇ, and Thomas J. Blacklock Process Research and DeVelopment, NoVartis Institute for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
Abstract: A concise large-scale synthesis of 1, a new antimitotic agent is described. The key step was a one-pot Sonogashira crosscoupling of an aryl halide with a heteroaryl halide through an acetylene using the readily available 2-methyl-3-butyn-2-ol (7). An innovative approach for palladium removal was designed and successfully scaled-up on a multikilogram scale. The product was crystallized from the crude reaction mixture while keeping the residual palladium in the mother liquor by using Pd-scavenging agents such as N-acetylcysteine or thiourea.
Scheme 1
Introduction Compound 1 is an antimitotic agent,1 which inhibits the proliferation of human epidermal cells, and it is being developed for topical treatment of hyperproliferative skin disorders with an improved therapeutic window and a reduced side-effect profile relative to the current standard treatment, i.e., topical treatment with 5-fluorouracil or surgical treatment. The first plant campaign was completed with the preparation of 3 kg of drug substance, and the second plant campaign was completed with the delivery of 50 kg of drug substance with an overall yield of 59% based on 2 by using an optimized Sonogashira coupling reaction2 as the key step for making the unsymmetrical bisarylethyne 3.
with the same aryl halide in the case of symmetrical diarylethyne or a different aryl halide for obtaining an unsymmetrical ethyne. Recently Grieco and co-workers3a published a one-pot synthesis applicable to both symmetrical and unsymmetrical ethynes using trimethylsilylacetylene ($5760/kg, Aldrich) and DBU/water for the in situ removal of the silyl group as shown in Scheme 1. This concept can be traced back to the in situ method introduced by Mori and co-workers earlier.3b We accomplished a similar one-pot preparation of 1 with a much less expensive and readily available acetone adduct of acetylene, namely 7 ($55/kg, Aldrich) in a more efficient manner, and these results are presented here. The original synthesis of 1 employed by medicinal chemists1 is shown in Scheme 2. This synthesis involves a Pd-catalyzed coupling of aryl acetylene 5 with heteroaryl halide 2 followed by hydrogenation. The aryl acetylene 5 was generated by a Wittig olefination, and a chromatographic purification was necessary as triphenylphosphine oxide was formed as a byproduct in stoichiometric amounts. This was a scale-up problem. However, the coupling of acetylene 5 with 2 as reported in the original synthesis could be retained for large-scale work. On the basis of a retrosynthetic analysis, of 5 we came up with commercially available 6 (bulk price
