Danuglipron (PF-06882961), a potent, orally bioavailable small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, is currently being developed for glycemic control among patients with Type-2 diabetes (J. Med. Chem. 2022, 65, 8208-8226; JAMA Netw. Open. 2023; 6(5): e2314493). The earlier synthesis of danuglipron suffered from chemoselective issues due to the competing nitrile hydrolysis in the final saponification step, which resulted in highly convoluted operations and extensive chromatographic purifications. We found that the methyl ester could be converted to trifluoroethyl ester, and the latter underwent hydrolysis to carboxylic acid in a much cleaner reaction profile. A thorough design of experiments (DOE) was conducted to expand the operating time window of the process to aid the process robustness during manufacturing. The improved process increased the yield by similar to 20% and reduced the process mass intensity (PMI) by 86%.

Process development for the synthesis of a second generation beta-amyloid-cleaving enzyme (BACE1) inhibitor (1) is described. The lithiothiazole addition to the isoxazolene (5) under batch conditions was not scalable because of reaction gelling and anion instability. A continuous stirred-tank reactor flow process was developed and successfully executed on the 70 kg scale in multiple runs. In a head-to-head comparison between the continuous and batch processes, the former was clearly superior as it gave a higher yield (80 vs 63%) of the adduct (4) and better reaction control for handling the unstable lithiothiazole as a reaction intermediate. Subsequently, 4 underwent Pd-catalyzed amination with t-butyl carbamate, reductive cleavage of the N-O bond, thioamidine cyclization, and deprotection of the Boc group to provide hydropyranothiazine 2. The synthesis of 1 was completed by amidation with 5-(difluoromethoxy)picolinic acid and the successive deprotection of the benzamide group with either Silicycle-diamine or L-lysine.

Radical fluoroalkylation is a powerful synthetic tool for the late-stage incorporation of fluorinated moieties into organic molecules, which is widely used in the development of pharmaceuticals and agrochemicals. Here, we report an efficient radical chlorodifluoromethylation protocol with sodium chlorodifluoromethanesulfinate, which is complementary to the existing late-stage difluoromethylation strategies. CF2Cl radical is a suitable surrogate for accessing the CF2H group while possessing completely different electronic properties compared to the CF2H radical. This method is chemoselective and regioselective for the chlorodifluoromethylation of (hetero)arenes and electron-rich alkenes and shows good functionality, tolerance, and generality on scope. The preparation of the sodium chlorodifluoromethanesulfinate is thoroughly investigated and can be scaled up to hundreds of kilograms. The method is successfully implemented on the synthesis of an oncology candidate compound 1.

A multistep continuous manufacturing process to synthesize (1R,2R)-2-amino-1-methylcyclopentan-1-ol (2) was developed. The step 1/2 flow process mitigated the safety hazard associated with high exothermicity during epoxidation, the epoxide-opening reaction, and the low onset of the epoxide intermediate. Process improvements included a hybrid plug flow reactor (PFR)/continuous stirred tank reactor (CSTR) reaction and a continuous quench/work-up process in step 1; a continuous reaction, extraction, washing, and thin-film distillation work-up in step 2; and a continuous trickle bed hydrogenation in step 3, which provided the desired product with high purity and high ee. The end-to-end continuous process provided significant advantages of cost-saving, minimization of manufacturing space and utilities, and reduction of the cycle time.

Mathematical modeling of chemical reaction kinetics has been proven to aid the development of new reactions and processes. Chemical kinetic modeling is a well-established principle in chemical engineering that uses fundamental knowledge of the reaction mechanism to predict conversion data. In pharmaceutical drug development, elementary-type kinetics are hardly common, because of the nature of the complex organic reaction mixtures and low-level impurities. Thus, data-driven modeling plays an important role in understanding the relationship between reaction parameters and reaction profiles. Advances in reaction automation technologies, such as high-throughput platforms and autosamplers, enable greater data collection to enrich our understanding of chemical reactions. As a result, statistical analysis has shifted from conventional end-point analysis to modeling the entire reaction profile using more advanced statistical models. Data-driven approaches are especially useful in early stage of development where not enough time or material is available for a proper kinetic model development. For the same modeling task, regardless of the underlying approach, we strongly feel that a systematic process of model development needs to be applied. We developed a rigorous and general modeling workflow describing how to apply kinetic models and statistical models to a set of dynamic reaction data. In particular, a semiparametric model was applied. An industrial case study is presented with a methyl ester chemoselective hydrolysis reaction, to showcase the performance and robustness of the two modeling approaches and their impacts, side by side, on parameter effect estimation, reaction robustness range finding, and reaction optimization and operation window prediction. New and innovative visualization techniques are shared in this article for efficient data and model result interpretation.

The process development of a nicotine analog or hapten (1) for conjugation to a protein as an antigen is described. The original process in early development used an Ir-catalyzed borylation reaction to enable rapid derivatization of nicotine with the desired regiocontrol. While the process was very efficient, it required chromatography to meet purity targets. A related process was later developed that possessed crystalline intermediates to better control levels of process-related impurities and heavy metals in 1. This control strategy for 1 was essential due to the strict purity requirements for conjugation of 1 when forming an antigen. In addition, the Ir-catalyzed borylation was studied to enable robust manufacture via this methodology which led to an efficient process for the preparation of 1.

This is the first in a series of three papers describing commercial manufacturing process development for palbociclib (1). This manuscript focuses on the SNAr coupling between aminopyridine 3 and chloropyrimidine 7. The regioselectivity of the SNAr coupling was studied from a synthetic and mechanistic perspective. Grignard bases were identified as the preferred class of bases for this reaction, allowing for a simplified process and reduced usage factor for aminopyridine 3. The development of this SNAr reaction into a scalable commercial manufacturing process is also described.

A three-step commercial manufacturing route has been developed for palbociclib, a highly selective, reversible inhibitor of CDK 4/6. The second step, which utilizes a Heck coupling to install the enol ether side chain, is described. A highly regioselective catalyst was identified for this transformation along with reaction conditions that ensure robustness upon scale-up. Effective removal of palladium was accomplished via filtration of insoluble metal and an extractive chelation step. Finally, efficient isolation of coupled product 3 was achieved through careful polymorph control via seeding and an optimized cooling protocol that avoids nucleation of a kinetically favored, slow-filtering polymorph.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSpecial Feature Section: Engineering Contributions to Process ChemistryDavid J. Lamberto, Mark T. Maloney, Saravanababu Murugesan, and Srividya Ramakrishnan*View Author Information Chemical Process Development and Commercialization, Merck Sharp & Dohme Corp., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States Chemical Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States Medication and Procedural Solutions, BD Medical, Becton Dickinson Co., 1 Becton Drive, Franklin Lakes, New Jersey 07417, United States Integrated Product Development, Dr. Reddy's Laboratories Ltd., Bachupally, Hyderabad 500090, India*E-mail: [email protected]Cite this: Org. Process Res. Dev. 2015, 19, 9, 1075Publication Date (Web):September 18, 2015Publication History Published online18 September 2015Published inissue 18 September 2015https://pubs.acs.org/doi/10.1021/acs.oprd.5b00254https://doi.org/10.1021/acs.oprd.5b00254editorialACS PublicationsCopyright © 2015 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views825Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (118 KB) Get e-AlertscloseSUBJECTS:Computational chemistry,Crystallization,Dissolution,Kinetics,Particle size Get e-Alerts

An optimized and scalable process to manufacture peptide–linker conjugate 1 is reported that avoids the chromatographic purification and lyophilization that are typically required for the isolation of this type of compound. An operationally simple protocol has been developed that couples the peptide to the linker in DMF followed by precipitation with MeCN. A scalable synthesis of the linker is also described which features the N-acylation of 2-azetidinone promoted by 1-propanephosphonic acid anhydride (T3P). The number of operations during the second step of the synthesis (nitrobenzene reduction to aniline) has been simplified by telescoping the aniline into the next step (reaction with diglycolic anhydride to form an acid), thus avoiding an additional isolation. Finally, two efficient activation methods for the acid have been developed by means of the corresponding pentafluorophenyl (PFP) and p-nitrophenyl (PNP) esters.

An efficient, scalable, and cost-effective synthesis of a linker employed in a bioconjugation process with a peptide and a monoclonal antibody is presented. Several routes were investigated that resulted in the identification of a short synthesis to a key acid intermediate from inexpensive and readily available starting materials. The final coupling of this acid with an aniline to afford the desired linker has been optimized to produce multi-gram quantities of material for clinical studies. The very limited purifications needed for both intermediates and final product make this route amenable to scale.

Agitated filter-dryers (AFDs) are commonly used for performing both filtration and drying operations in the manufacture of active pharmaceutical ingredients (APIs) and intermediates. Successful scale-up from the laboratory to manufacturing AFD equipment requires that physical properties specifications such as particle size be consistently met in addition to chemical purity specifications. Depending on the API solvent system and equipment operational parameters, undesired attrition or agglomeration may occur, so an improved understanding of these phenomena upon scale-up is of key importance. In this paper, we describe recent advances in laboratory methods, based on material characterization methods common to drug product formulation development, to better assess the risk of agglomeration and attrition potential upon scale-up. These methods provide data to evaluate solid behavior, in both wet and dry states, associated with processing in an AFD. For agglomeration prediction, the application of mixer torque rheometry for measuring the propensity to form granules or agglomerates of API wet cake is described as well as how to categorize agglomeration risk based on the output of this testing. For measuring attrition propensity, the application of powder rheometry is described, and risk categories are proposed. For both testing methods, good agreement was seen between laboratory predictions and actual behavior upon scale-up. For compounds evaluated as high risk for attrition or agglomeration, alternate drying protocols are recommended to mitigate risk. In addition, progress on enhancing cycle times for difficult to dry materials is discussed.

We describe the development of an efficient and scalable process for the preparation of fluorocyclobutane-containing H-3 antagonist, 1. The synthesis was accomplished by the chemoselective addition of a magnesium ate complex and an amine to a 1,4-ketoester in a one-pot sequence, followed by a diastereoselective carbonyl-directed fluorination. The chemoselective addition of the magnesium ate complex to the ketoester benefited from tight stoichiometric control, short addition times, and lower reaction temperatures, and thus was amenable to rapid mixing and excellent heat transfer in a flow reactor.

An optimized and scalable synthesis of a novel analytical reagent for the determination of the number of active sites available for conjugation on a catalytic aldolase monoclonal antibody (mAb) is described. The original conditions suffered from lack of reproducibility, incomplete reactions, and required several chromatographies and lyophilizations that afforded material of low purity. A redesigned route and optimized protocols have been developed that eliminate the use of toxic and unsafe reagents such as HMPA and HATU. In addition, the number of chromatographies has been reduced to only one and time-consuming and energy-intensive lyophilizations are no longer required. The overall yield has been considerably improved from the original 4% to 20% after telescoping the last two steps of the synthesis and this new approach allowed for the preparation of material with higher chemical purity (>= 99% vs the initial 90%) to meet specifications. (C) 2012 Elsevier Ltd. All rights reserved.

As part of Pfizer's continuing efforts in the oxazolidinone area, we have developed an efficient synthesis of PNU-288034 and successfully implemented it on pilot scale. The key step was a novel, acid-catalyzed, double Michael addition of 2,6-difluoroaniline with divinyl sulfone to install the desired dioxidothiomorpholinyl ring. Regioselective nitration provided the desired para-nitrogen, which was converted to the penultimate carbamate using standard chemistry. The resulting carbamate proved to be an excellent substrate for the recently reported oxazolidinone synthesis. As is normally the case, removing impurities to achieve our quality targets for API was a challenge, but unexpectedly, some impurities also caused significant processing difficulties as well. In the end, a safe and robust process was developed which provided clinical-quality material in five linear steps with an overall yield of 41% and was proven reproducible in multiple pilot-plant campaigns.

An efficient synthesis of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)-6-oxo-6H-pyrrol[3.2.1-ij]quinoline-5-carboxamide (5) was developed. The route was chosen due to its reasonable length (seven steps), solubility of intermediates, and capabilities of the pilot and production facilities. The critical transformations in this route were the selective iodination of an aniline, formation of the quinolone, and Sonogashira coupling/pyrrole formation. In addition, removal of residual palladium and copper from the penultimate and final products, which was of lower concern during the discovery phase of development, became a difficult process chemistry issue on scale-up.