An Improved Impact Ratio for Identifying Critical Process Parameters in Pharmaceutical Manufacturing Processes.

The identification of critical process parameters in biologics and small molecule process development is a key element of quality by design. The objectivity and consistency of procedures to identify critical process parameters can be improved with the use of impact ratios. Impact ratios quantify a process parameter's practical effect on a critical quality attribute relative to the critical quality attribute's acceptance limits.

Stereoselective Synthesis of the IDO Inhibitor Navoximod.

A highly efficient asymmetric synthesis of the IDO inhibitor navoximod, featuring the stereoselective installation of two relative and two absolute stereocenters from an advanced racemic intermediate, is described. The stereocenters were set via a crystallization-induced dynamic resolution along with two selective ketone reductions: one via a biocatalytic ketoreductase transformation and one via substrate-controlled hydride delivery from LiAlH(OBu). Following this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde and isolated in 23% overall yield with 99.

Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin.

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

Efficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(I)-catalyzed [3+2] Asymmetric Cycloaddition.

A concise asymmetric synthesis has been developed to prepare idasanutlin, a small molecule MDM2 antagonist. Idasanutlin is currently being investigated as a potential treatment for various solid tumors and hematologic malignancies. The highly congested pyrrolidine core, containing four contiguous stereocenters, was constructed via a Cu(I)/(R)-BINAP catalyzed [3+2]-cycloaddition reaction.

Novel Series of Dihydropyridinone P2X7 Receptor Antagonists.

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.

Studies of new indole alkaloid coupling methods for the synthesis of haplophytine.

[reaction: see text] The two novel bisindole alkaloid structures shown can be synthesized in a few steps from the canthiphytine derivative 9.

Impact of the C1' configuration of abasic sites on DNA duplex structure.

Naturally occurring abasic sites in DNA exist as an equilibrium mixture of the aldehyde, the hydrated aldehyde, and the hemiacetal forms (dominant). The influence of the configuration of the C1' hydroxyl group of the hemiacetal form on duplex structure and abasic site repair has been examined using novel carbocyclic analogues. Both the alpha- and beta-forms of this novel abasic site were introduced into oligomeric DNA using the standard DMT-phosphoramidite approach in an automated solid-phase synthesizer.

Simple, catalytic enantioselective syntheses of estrone and desogestrel.

Highly enantioselective and very short syntheses of the bioactive forms of estrone (3) and desogestrel (4) are described using a chiral oxazaborolidinium catalyst (2) in the key initial step. Enantiomerically pure estrone was synthesized in eight steps from the readily available starting materials diene 5 and alpha,beta-enal 6 via intermediates 8 and 9. Desogestrel was synthesized using a similar strategy from diene 5 and alpha,beta-enal 11 via intermediates 12-17.

Application of vicarious nucleophilic substitution to the total synthesis of dl-physostigmine.

A concise, highly efficient formal total synthesis of dl-physostigmine is described, using a relatively simple method that should be adaptable to the synthesis of homologous members of this type of alkaloid. The key step in the synthesis is a new vicarious nucleophilic substitution reaction between p-nitroanisole and a C-silylated derivative of N-methylpyrrolidinone. Subsequent conversion of the initial adduct to the tricyclic framework of physostigmine follows a well-established protocol and provides the key intermediate 8 in high yield.

Spray-dried chitinosans. Part II: in vitro drug release from tablets made from spray-dried chitinosans.

Purpose: Application of spray-dried chitinosans as excipients for use in drug delivery systems was explored.

Methods: Spray- and tray-dried chitinosans previously N-deacetylated and depolymerized were used. Directly compressed tablets (200mg) containing tetracycline, chitinosan, and magnesium stearate were prepared.

Spray-dried chitinosans. Part I: preparation and characterization.

Purpose: Physicochemical and micromeritic characterization of chitinosans.

Methods: Chitinosans subjected to N-deacetylation and depolymerization were characterized for degree of N-deacetylation (DD), molecular weight (MW), pK(a), particle size determination and morphology, tap/bulk density measurements, surface area determinations, and determination of flow properties.

Results: The chitinosan DDs and MWs were dependent on the processing conditions and ranged from 66 to 89% and 2-522 kDa, respectively.

Chitinosan-drug complexes: effect of electrolyte on naproxen release in vitro.

The purpose of this study was to examine the potential use of electrolytes to control naproxen sodium (I) release from chitinosan (II) tablets. An ANOVA was employed to evaluate the effects of molecular weight (MW) of II, electrolyte valence (EV), and pH of the dissolution medium on I's release. The intrinsic dissolution rates and saturation solubilities of I were determined at each of the pHs used.

The effect of Lewis bases on the (13)c NMR of iodoalkynes.

In Lewis-basic solvents, alkynyl carbons bonded to iodine have chemical shifts approximately 12-15 ppm higher in frequency than the corresponding shifts in CDCl3. We offer computational evidence that this solvent effect comes directly from polarization of the iodoalkyne triple bond. Hartree-Fock and Density Functional Theory calculations reproduce the change in chemical shift for a gas-phase complex between the iodoalkyne and dimethyl sulfoxide as Lewis base.