Potential Inhibitors of Tyrosine Kinase 2: Synthesis of Important Intermediates

Abstract

Two different synthesis routes towards target molecule 1 have been investigated. Synthesis route A (see Figure II) is based on previous work by Ragnhild G. Ohm and Cecilie Surdal. This route gave a total yield of 20% for the synthesis of compound 3, in a Z/E-mixture in the ratio 1:0.9. The Z/E-mixture was inseparable by column chromatography (except a small amount of the E-isomer), hence a new synthesis route was contemplated.Synthesis route B was developed to enable synthesis of enantiomerically pure substrates for use in Suzuki -and Hiyama cross-couplings, towards target molecules (E)-1 and (Z)-1. The first step with condensation between methylpropiolate (18) and arylaldehydes 17a and 17b was accomplished with yields of 46% and 52% respectively (see Figure III).The second step was a protection of propargylic alcohols 16a and 16b with TBDMSCl. This reaction gave yields of 63% and 64% respectively. Subsequent hydrosilylation of the protected 15a to (E)-14a was attempted, but NMR showed unreacted 15a. Attempts on hydrosilylation of compound 16a and 16b gave a complex mixture and no insulatable product.The Ritter reaction for amidation of the propargylic alcohol 16a was attempted, but 1H NMR showed unreacted starting material.