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.
An efficient, safe, and cost-effective synthesis of 2-methyltryptamine (2), a key starting material in the synthesis of the histone deacetylase inhibitor LBH589 (1) is described. The reaction of phenylhydrazine (7) with a stoichiometric amount of 5-chloro-2-pentanone (8) in aqueous ethanol at reflux furnished crude 2-methyltryptamine (2). The product 2 was obtained in 47% yield and >99% purity after crystallization from toluene.
LAB687 is an inhibitor of microsomal triglyceride transfer protein (MTP) designed to lower triglycerides and LDL cholesterol. The discovery of its polymorphic forms closely intertwines with the synthesis development of the molecule. At the early development stage, LAB687 was known to crystallize in two modifications, Forms A and B. Knowledge of the molecule’s polymorphic nature prompted extensive polymorphic screening using drug substance produced by the earlier synthesis routes. These studies revealed the existence of a third polymorph, Form C. Subsequently, Form C was selected for further development based on data from the additional formulation and polymorphic studies. Surprisingly, a new modification, Form D, appeared when the crystallization process known to routinely produce Form C was scaled up in the pilot plant. Once Form D was introduced to the laboratory, Forms A and C could no longer be made. We hypothesize that a change in drug substance impurity profile due to the changes in synthesis, led to the emergence of the most stable Form D.
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