The development of a factory process to manufacture the novel cardiac myosin activator omecamtiv mecarbil (1) is described. Omecamtiv mecarbil is prepared via the convergent synthesis and coupling of two key fragments, aniline 2 and carbamate 4-HCl which serves as a masked isocyanate. To enable practical access to aniline 2, reduction of the corresponding nitroaromatic was designed to control potential mutagenic impurities. Key to the efficient preparation of 2 was the benzylic bromination of 8 followed by selective debromination of a gem-dibromide byproduct and subsequent alkylation with 5-hosphate. Overall, the longest linear sequence consists of six steps, including a,final salt formation step to afford the drug substance in 55% overall yield. Because of poor performance of the original free-base form of the drug substance in modified release formulations, an improved dihydrochloride hydrate form was developed to aid drug product performance and manufacturabiity.

By using the solution NMR technique and the "cleave and analyze" approach, we have modeled the kinetics of coupling reactions between activated Fmoc-Arg(Pbf)-OH and NH2-Arg(Pbf)-Arg(Pbf)-Ala-Arg(Pbf)-Rink amide-AM resin, determined the reaction rates, and correlated the extent of conversion to the Kaiser and TNBS color test results. Since NMR spectroscopy is a highly specific and quantitative tool with structural elucidation capability, the NMR assay for determination of the reaction conversion in solid-phase peptide synthesis (SPPS) can be developed by comparing the peaks from the reactant peptide containing the free amino groups with the product peptide containing the newly coupled Fmoc-amino acid moiety in the one-dimensional H-1 NMR spectrum. We utilized the NMR assay to measure the conversion for each cycle in SPPS to assemble Ac-c(C)arrrar-NH2 and provided an in-process testing (IPT) time limit for the full-scale production. The data showed that after 18 h of reaction, the conversion for all cycles achieved >99.9%, demonstrating the robustness of the SPPS process and ensuring the control of certain impurities, such as deletion sequences, below 0.1% in the active pharmaceutical ingredient.

An expeditious synthetic approach to chiral phenol 1, a key building block in the preparation of a series of drug candidates, is reported. The strategy includes a cost-effective and readily scalable route to cyclopentanone 3 from isobutyronitrile (10). The sterically hindered and enolizable ketone 3 was subsequently employed in a challenging Grignard addition mediated by LaCl(3)·2LiCl. A novel preparation of the lanthanide reagent required for this transformation is described. To complete the process, a highly enantioselective hydrogenation step afforded the target (1). The importance of the phenol group to the success of this asymmetric transformation is discussed.

AbstractAn effective route to chiral cyclopentanes (II), useful precursors of a series of drugs, is reported.

A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room temperature in the presence of [(t-Bu(3)P)PdBr](2) providing products in up to 37:1 dr.

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A synthesis of EPO 22–37 glycopeptide (1), presenting the N-linked dodecasaccharide of erythropoietin, is described.

A synthesis of the protected biantennary N-glycan of the naturally occurring glycoprotein, erythropoietin, is described.

A series of 2-alkylsulfonyl-2'-biphenyl radicals, in which the alkyl group is primary, secondary, or tertiary, were generated and the products of their reactions investigated. Dibenzothiophene S,S-dioxide was not identified among the products, which arose mainly from intramolecular hydrogen abstraction from the alkyl group or addition to the solvent, benzene. On this basis, it is concluded that homolytic substitution at sulfonyl sulfur, if possible at all, is too slow to take precedence over a number of competing decomposition pathways. Previous literature results suggesting the possibility of intramolecular homolytic substitution at sulfonyl sulfur may be explained by alternative processes.

A series of 12 stereochemically defined 2,m-dimethyl- and 2,m,n-trimethyl-6-benzylamino-2-nitro-3-(diphenylphosphatoxy)hexanes have been synthesized and their cyclization reactions leading to di- and trisubstituted N-benzyl pyrrolidines examined in the presence of tributyltin hydride and azoisobutyronitrile in benzene at reflux. The cyclizations are interpreted in terms of generation of an alkyl radical by abstraction of the nitro group with a stannyl radical. The phosphate leaving group is then expelled in a heterolytic cleavage to give a contact alkene radical cation/phosphate anion pair. For the majority of the examples studied, the cyclizations are best understood in terms of nucleophilic attack by the amine on the opposite face of the alkene radical cation to the one shielded by the leaving group, within the confines of the initial contact ion pair, resulting in overall cyclization with inversion of configuration. Dependent on the relative stereochemistry of the substituents, the cyclization is envisaged as taking place through either chair-like or twist-boat-like transition states with the maximum number of substituents pseudo-equatorial. The model breaks down when cyclization on the initial contact ion pair would engender significant destabilizing steric interactions, especially (1,3)A strain in the alkene radical cation. In these cases a fully equilibrated Beckwith-Houk-type transition state provides a satisfactory model. Interesting examples of matching and mismatching in the Corey-type oxazaborolidine-mediated reduction of alkyl (methyl-1-nitroethyl) ketones by a beta-methyl group in the alkyl chain are reported, and the mismatching is attributed to a developing syn-pentane interaction in the transition state.

It is demonstrated that phosphorylated forms of beta-nitro alcohols provide an excellent means of entry into beta-(phosphatoxy)alkyl radicals on exposure to tributyltin hydride and AIBN in benzene at reflux. These radicals then undergo heterolytic cleavage of the phosphate group to yield alkene radical cation/phosphate anion contact ion pairs which are trapped intramolecularly in a tandem polar/radical crossover sequence involving radical ionic chain reactions by allylic and propargylic amines. The substitution pattern of the alkene radical cation dictates the cyclization mode, and this may be engineered to form fused ring systems by an initial exo-mode nucleophilic cyclization or bridged bicyclic systems when the nucleophilic attack takes place in the endo-mode.

It is demonstrated that alpha,alpha-disubstituted-alpha-nitroketones are reduced to the corresponding trisubstituted nitro alcohols in good to excellent yield and enantiomeric excess by borane-dimethyl sulfide in the presence of a chiral oxazaborolidine catalyst. Reduction of the nitro alcohols to the corresponding amino alcohols and their subsequent conversion to enantiomerically enriched 4,4,5-trisubstituted oxazoldinones is also reported.

A series of highly diastereomerically enriched 1,5-dimethyl-, 2,5-dimethyl-, and 3,5-dimethyl-N-benzyl-5-nitro-4-(diphenylphosphatoxy)hexylamines were exposed to tributyltin hydride and AIBN in benzene at reflux. The ensuing reactions, interpreted in terms of radical denitration, radical ionic fragmentation, and nucleophilic substitution, lead to the formation of pyrrolidines with moderate to high diastereoselectivity. In five out of the six cases, the diastereoselectivity is best interpreted by backside attack by the amine on the initial contact ion pair generated by radical ionic fragmentation. In the exception that proves the rule, this mode of attack is disfavored by 1,3A strain in the initial contact ion pair, resulting in equilibration and subsequent attack on the opposite face.

[see reaction]. Stable beta-phosphatoxy nitroalkanes, readily assembled by the Henry reaction and subsequent phosphorylation, serve as good precursors to alkene radical cations on treatment with triphenyltin or tributyl hydride and AIBN in benzene at reflux. When the beta-phosphatoxy nitroalkane is suitably functionalized with nucleophilic groups, substitutions can be achieved with the formation of heterocyclic rings. When the nucleophile is an allylamine, tandem processes occur giving pyrrolizidines.