This report describes a new convergent, selective, and economical synthesis of DMP 777, 1 ending with the coupling of the chiral -lactam half of the molecule (1) to the chiral amine as the isocyanate (2). Other steps involve the coupling of the -lactam 3 to the phenolic moiety under phase-transfer conditions, followed by resolution of the resulting piperazine derivative using a chiral acid, and recycling of the undesired enantiomer also under phase-transfer conditions. The chiral amine 4 was produced efficiently starting from (R)-r-methylbenzylamine and the corresponding butyrophenone.Contemporary pharmaceuticals often contain multiple chiral centers which provide a significant challenge to the process chemist. Fortunately, an array of tools is now available to address absolute stereochemistry, including classical resolution, chiral auxiliaries, asymmetric catalysis, and enzyme resolution. It is increasingly evident that no single method is consistently superior. A thorough approach to process development requires the consideration of all available chiral technologies to provide the most efficient route to a given drug candidate.DMP 777, an inhibitor of leukocyte elastase, could prevent degradation of the structural proteins elastin and collagen, a process implicated in cystic fibrosis and rheumatoid arthritis. 2 Retrosynthetic analysis indicates that DMP 777 should be accessible by coupling two enantiopure fragments, -lactam 1 and isocyanate 2 (Figure 1). Potentially, -lactam 1 may derive from the commercially available racemic lactam 3. 3 Consequently route-development efforts focused on identifying efficient conditions for elaboration of 3 into racemic 1, and its subsequent resolution. The precursor to isocyanate 2, amine 4, is not an article of commerce; therefore, a process from simple materials had to be devised. We will discuss in turn the synthesis of fragments 1 and 2 and conclude by describing a procedure for their efficient coupling.A short convergent process required a practical synthesis and resolution of the -lactam portion (Scheme 1). The reaction conditions had to be balanced to provide the requisite basic elimination of propionic acid from 3 to give the reactive 3,3-diethylazetin-2-one, 5, without hydrolysis of lactam. Phase-transfer catalytic conditions using a tetrabutylammonium salt gave the most efficient reaction, with an isolated yield of 88%. 4 About 25 chiral acids were screened for utility in the resolution. Diacetoneketogulonic acid (DAG) gave by far the best resolution, with the R-enantiomer DAG salt crystallizing out in high ee and thus overcoming a 10-bond separation between amine group and the chiral center. The S-isomer was then easily precipitated, DAG was recovered, and the R-isomer was racemized under phase-transfer conditions similar to those for its original synthesis (conversion of 3 to 1-racemate). Clarke, G. D. E.; Dowle, M. D.; Harrison, L. A.; Hodgson, S. T.; Inglis, G. G. A.; Johnson, M. R.; Shah, P.; Upton, R. J.; Walls, S. B. J. Org. Chem. 1999, 64, 5166-5175 and ref...

This report describes the large-scale synthesis of 1 that features a Fischer indole strategy to form an advanced intermediate followed by reduction to the indoline to construct the tetracyclic core of the molecule. Resolution using dibenzoyl-D-tartaric acid affords access to a single enantiomer, from which a Suzuki coupling builds in the biaryl functionality. Deprotection followed by salt formation furnishes the desired target molecule.

Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process for manufacture of preclinical and clinical supplies is discussed. Details regarding a blocking group strategy for selective nitration; discovery of a one-pot transfer hydrogenation to effect a reductive amination, nitro group reduction, and dehalogenation; an enzymatic resolution of a critical intermediate; and the discovery of a novel, stable, in situ generated mixed mesylate hydrochloride salt of the API are disclosed.