The aniline derivative 3 is a key building block of rilpivirine (TMC278) 2, a new potent NNRTI compound under clinical evaluation. In this paper we describe the development of a new synthesis of 3 based on a Heck coupling between a halogenated aniline and acrylonitrile using low loading of Pd/C (0.5 mol %) as catalyst. This resulted in a process which has been successfully transferred into production on 2400 mol-scale (6000 L reactor)
A new class of orthoacylimine-derived chiral auxiliaries has been synthesized and tested in the nucleophilic addition of organolithium reagents to imines. The precursors can be prepared by an aza-Wittig reaction between the corresponding orthoacyl azide and a variety of aldehydes in the presence of trialkylphosphines. The nucleophilic addition of organolithium reagents led to the addition products in good yields and with good to excellent diastereoselectivities (from 85:15 to 99:1). The chiral, nonracemic secondary amines could be readily obtained under mild hydrolytic condition. Furthermore, the chiral auxiliary can be recovered in quantitative yield and reconverted to the starting orthoacyl azide precursor. This method was applied to the synthesis of (S)-t-leucine.
Imines. -A novel class of chiral auxiliaries for the nucleophilic addition of organometal compounds to imines is presented. Thus, condensation of optically active diols (I) and (XIII) with orthoformate and trimethylsilyl azide provides orthoacyl azides (III) and (XIV), resp., which smoothly undergo aza-Wittig reaction with various aldehydes in the presence of trimethylphosphine to furnish the title orthoacylimines (V), (X) and (XV). The nucleophilic addition of organometal compounds is achieved only with organo-lithium compounds, while Grignard reagents and organo-copper reagents do not react. The addition proceeds with moderate to high diastereoselectivity depending on the complexing properties of the solvent used. Acidic hydrolysis of the primary adduct [cf. (VII)] provides an effective access to enantiomerically enriched secondary amines, e.g. (VIII) and (XII). The auxiliary diol (I) is recovered in excellent yield. Derivative (XIId) is transformed into (S)-leucine in four steps. -(BOEZIO, A. A.; SOLBERGHE, G.; LAUZON, C.; CHARETTE*, A. B.; J. Org. Chem. 68 (2003) 8, 3241-3245; Dep. Chem., Univ. Montreal, Montreal, Que. H3C 3J7, Can.; Eng.) -Mischke 36-020 2003 Diastereoselective syntheses
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