Asaad S. Nematalla

Early Development of Ibuzatrelvir: Navigating Polymorph and Crystallization Challenges in a Protecting Group-Free Direct Amidation and Amidation-Dehydration Sequence

María González‐Esguevillas, Aaron F. Baldwin, Pablo J. Cabrera, Yanfei Guan et autres

Abstract Ibuzatrelvir is an orally bioavailable, next-generation clinical candidate developed for the treatment of COVID-19 infections. It was identified during the pandemic, prior to the approval of PAXLOVID, and displays a more favorable pharmacokinetic profile than nirmatrelvir. Consequently, the initial development of …

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Development and Optimization of a Scalable Palladium-Catalyzed C–N Coupling and Acid-Catalyzed Protecting Group Removal Telescope Process for the Synthesis of CDK2-Selective Candidate Tegtociclib (PF-07104091)

Tyler J. Potter, Thomas A. Brandt, Robert David Bright, Yiqing Feng et autres

PF-07104091 is a cyclin-dependent kinase 2 (CDK2)-selective inhibitor under investigation as an oncology treatment with breast cancer as the leading indication. In this report, we detail the process development and optimization of a telescoped palladium-catalyzed C–N coupling and acid-catalyzed protecting group removal. …

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Development and Optimization of a Scalable Enzymatic Cascade-Carbamate Formation Telescope Process for the Synthesis of CDK2 Selective Candidate Tegtociclib (PF-07104091)

Kaitlyn C. Gray, Thomas A. Brandt, Robert David Bright, Michael P. Burns et autres

PF-07104091 (tegtociclib) is a cyclin-dependent kinase 2 (CDK2) selective inhibitor under investigation as an oncology treatment with breast cancer as the leading indication. In this report, we detail the development and optimization of a selective enzyme cascade-carbamate formation telescoped sequence for the …

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Exploratory Process Development of a Pulmonary Arterial Hypertension Clinical Compound via a Late-Stage Pd-Catalyzed Buchwald–Hartwig C–N Coupling

Yiyang Liu, Sébastien Monfette, Russell F. Algera, Andrew Davidson et autres

Abstract The development of a robust process for a Pd-catalyzed Buchwald–Hartwig C–N coupling reaction to manufacture PF-06842874, a clinical candidate for the treatment of pulmonary arterial hypertension, on kilogram scale is reported. The variability in reaction kinetics initially encountered was resolved via …

Route Optimization of the Non-covalent Modulator of Hemoglobin PF-07059013 for the Treatment of Sickle Cell Disease, Part I: From Discovery Synthesis to First Kilogram-Scale Manufacture

Aaron F. Baldwin, Shawn Cabral, Kris N. Jones, Jeffrey T. Kohrt et autres

The scalable route to PF-07059013 ( 3 ), a non-covalent modulator of hemoglobin for the treatment of sickle cell disease, is discussed. Optimization of the discovery route is presented, examining bond connections, late-stage Buchwald–Hartwig C–O coupling, and palladium content reduction strategies. The …

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Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors

Bryan Li, Richard W. Barnhart, Amélie Dion, Steven M. Guinness et autres

Process development for the synthesis of a second generation β-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 …

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CCDC 1940697: Experimental Crystal Structure Determination

Anne C. Akin, Mark T. Barilla, Thomas A. Brandt, John J. Brennan et autres

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, …

Overcoming the Challenges of Making a Single Enantiomer N-1 Substituted Tetrazole Prodrug Using a Tin-Mediated Alkylation and Enzymatic Resolution

Anne C. Akin, Mark T. Barilla, Thomas A. Brandt, John J. Brennan et autres

The synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor 3 is described. This complex structure contains a tetrazole modified by a chiral hemiaminal carbonate prodrug. A regioselective tin-mediated alkylation was utilized to access the N-1 alkylated tetrazole isomer, and a highly …

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Exploratory Process Development of Lorlatinib

Bryan Li, Richard W. Barnhart, Jacqui E. Hoffman, Asaad S. Nematalla et autres

The original synthesis of lorlatinib ( 1 ) was applied and improved in the first GMP campaign. In this approach, a slow addition of the boronate ester was critical in suppressing the formation of a homocoupled impurity in the Suzuki–Miyaura coupling, and …

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Exploratory Process Development of a Novel Diacylglycerol Acyltransferase-1 (DGAT-1) Inhibitor

Andrei Shavnya, Yong Tao, Susan C. Lilley, Kevin B. Bahnck et autres

A practical large-scale synthesis was developed for 1, a DGAT-1 inhibitor, involving an aza-Michael reaction, amidation, Dieckman cyclization, and conjugate addition of cyanamide followed by cyclization, to form the fused 4-amino-7,8-dihydropyrido[4,3- d ]pyrimidin-5-one scaffold. The enabled process presented here substantially improved safety …

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Efficient Synthesis of 4-Amino-2-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-5-ones: Practical Access to a Novel Chemotype in the Development of DGAT-1 Inhibitors

Kevin B. Bahnck, Yong Tao, Andrei Shavnya, Susan C. Lilley et autres

A practical access to an unprecedented, fused bicyclic 4-amino-2-alkoxy-7,8-dihydropyrido[4,3- d ]pyrimidin-5-one scaffold is developed. The synthesis of the potent inhibitor, 2-{4-[4-amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3- d ]pyrimidin-6(5 H )-yl]phenyl}-2-methylpropanamide is detailed, with particular emphasis placed on synthetic efficiency and scalability. With the isolation of solid intermediates, …

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Discovery of 5-[5-Fluoro-2-oxo-1,2- dihydroindol-(3 Z )-ylidenemethyl]-2,4- dimethyl-1 H -pyrrole-3-carboxylic Acid (2-Diethylaminoethyl)amide, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial and Platelet-Derived Growth Factor Receptor Tyrosine Kinase

Li Sun, Chris Liang, Sheri Shirazian, Yong Gui Zhou et autres

To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the …