The multihundred-gram synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine (1) is described utilizing a Stille cross-coupling of an iodothienopyridine (3) with 5-(tributylstannyl)-1-methylimidazole (11). Several cross-coupling methods were evaluated for the conversion of thienopyridine 3 to imidazole-thienopyridine 2, but only two were effective: the Stille coupling and a Negishi cross-coupling of the organozinc reagent derived from 2-(tertbutyldimethylsilyl)-1-methylimidazole and iodothienopyridine (3). The latter procedure worked well on laboratory scale (<50 g), but was capricious upon scale-up. The issues with scale-up of an organostannane reagent are discussed, including control and analysis of organotin levels.

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Converting iodoanilines to the corresponding 2,5-dimethylpyrroles was found to facilitate CuCl-mediated methoxide substitution. Examples with ortho-, meta-, or para-relationships between the iodide and aniline are presented. Several other aniline blocking groups were investigated and found not to be successful in this sequence.We recently required a practical, multigram synthesis of 2-fluoro-4-methoxyaniline (1) . The published synthesis of this compound 1 involves a nonselective nitration of 3-fluorophenol, 2 which was unacceptable for our purposes due to both safety considerations and the difficulty of separating the resulting mixture of regioisomers. Presented herein is a practical, regiospecific synthesis of 1 which also provides access to a variety of other methoxyanilines.Copper-mediated alkoxide substitution of aryl halides is a well-precedented method for the preparation of anisoles. [3][4][5] For the case at hand, the commercial availability of 2-fluoro-4-iodoaniline (Aldrich catalog #30,660-6, $73/100 g) made this an attractive route. The influence of an unprotected aniline in this reaction was unclear; a single literature report found that free NH 2 or OH groups on the aryl halide had a deleterious effect (yields of 35-50%, vs 75-100% yields for nonacidic substrates). 6 Indeed, when unprotected 2-fluoro-4-iodoaniline was exposed to NaOMe (3 equiv) and CuI (0.20 to 2.0 equiv) in MeOH/ DMF or pyridine, no substitution products were observed (Scheme 1, R 1 = R 2 = H).

Several synthetic approaches to a corticotropin-releasing factor (CRF) antagonist containing a tetrasubstituted pyridine were evaluated. In particular, nucleophilic aromatic substitutions on 2,4-dichloropyridine derivatives were attempted using 2,6-dimethyl-4-chlorophenol (4), (S)-2-aminobutanol (7), and several sulfur nucleophiles. It was found that a copper-mediated coupling of a phenoxymesylate (26) was preferred for preparation of the diarylether followed by nucleophilic aromatic substitution to introduce the amine side chain, affording the desired drug candidate (1) in two steps from the commercially available methyl 2,4-dichloro-6-methylnicotinate (2).

A scalable synthesis of CE-157119 HCl salt (1), an SRI/5-HT 2A antagonist, was developed via the regioselective S N Ar etherification between a phenol and an N-methylamide. This early development route shortened the original 5-step synthesis to three steps, eliminated all chromatography and increased the overall yield from 15% to 34%. The process was implemented for API manufacture from 100-g scale to multikilogram scale.