Reaction Chemistry & Engineering, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 18, 2024
A generalizable active learning framework enables accurate prediction of mass transfer coefficients ( k L a ), and iterative design experiments to efficiently characterize new reactor configurations with minimal experimental trials.
Language: Английский
Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(13)
Published: Jan. 27, 2024
Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising a range of oxidations, practical use enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering application non-heme iron α-ketoglutarate-dependent dioxygenase direct stereo- regio-selective non-native fluoroindanone en route to oncology treatment belzutifan, replacing five-step chemical synthesis with enantioselective hydroxylation. Mechanistic studies indicated that formation desired product was enzyme overoxidation, these properties subsequently improved directed evolution, yielding biocatalyst capable >15,000 total turnovers. Highlighting industrial utility this biocatalyst, high-yielding, green, efficient oxidation demonstrated at kilogram scale belzutifan.
Language: Английский
Citations
29
Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 422 - 431
Published: Feb. 1, 2024
Belzutifan (MK-6482) is an FDA-approved hypoxia inducible factor 2α inhibitor for the treatment of Von Hippel–Lindau disease-associated renal cell carcinoma. One key synthetic steps enzymatic benzylic hydroxylation indanone. Prior to optimization, reactions required dilute conditions (100 volumes water) and high enzyme loading (50 wt %) achieve target conversion, which was unsuitable a long-term manufacturing process. Reduction reaction introduced additional complexity large-scale operations due low solubility components. In addition development, it also necessary find optimal method protein residue removal from mixture isolate high-quality product. We present here our efforts overcome these challenges ultimately successfully developed, optimized, demonstrated at multikilogram scale process with improved mass intensity using only 7.5 % enzyme, 25 water, 1-octanol as unique additive.
Language: Английский
Citations
10
Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 413 - 421
Published: Jan. 30, 2024
A nickel-catalyzed sulfonylation reaction was discovered and developed into a robust process for the manufacturing of belzutifan, an FDA-approved treatment Von Hippel-Lindau disease-associated renal cell carcinoma. The proceeds via reductive sulfinylation utilizing two insoluble salts (potassium metabisulfite potassium formate), followed by methylation with nontoxic methylating reagent (trimethylphosphate). doubly heterogeneous nature proved difficult to scale due mixing particle size issues. Controlled addition solution formate in ethylene glycol found mitigate all scaling issues, mechanistic studies revealed this be control catalyst speciation. demonstrated on multikilogram kinetics between scales. Reaction discovery, development, multikilogram-scale demonstration, insights are detailed within.
Language: Английский
Citations
7
Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 432 - 440
Published: Feb. 1, 2024
Belzutifan has been approved recently by the U.S. Food and Drug Administration (FDA) for treating patients with certain types of Von Hippel-Lindau (VHL) disease-associated tumors. Although a commercial synthetic process established to make belzutifan, further optimized fewer steps, improved cost-effectiveness, smaller environmental footprint is always in demand. In new route, single-step biocatalytic hydroxylation reaction was used replace five chemical steps required previous route. developing this reaction, multiple analytical technologies (PATs), such as Fourier transform infrared spectroscopy (FTIR), situ imaging, dissolved oxygen monitoring, etc., were track important parameters under complex conditions (e.g., multiphases dense slurry). With quantitative modeling, product concentration yield can be tracked real time based on FTIR. This particularly slurry reactions, which offline sampling becomes challenging due sample inhomogeneity. In-depth mechanistic insights also obtained using PATs revealing kinetics controlled different mass transfer limited processes, well unique role 1-octanol. These PAT-enabled capabilities tracking understanding facilitated development from laboratory pilot scale ensured robust reaction.
Language: Английский
Citations
5
Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 441 - 450
Published: Feb. 7, 2024
A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced precious metal catalyst with ketoreductase (KRED) in the DKR. Achieving this one-pot reaction required several rounds enzyme evolution that improved stability presence acetonitrile and methanol. To maintain development progress satisfy program timelines, around reaction, workup, isolation operations performed parallel ongoing modification, as variants were made available. Additionally, opportunities improvements to product quality robustness identified by resolving issues observed piloting experiments.
Language: Английский
Citations
5
Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 451 - 459
Published: Feb. 5, 2024
A convergent nucleophilic aromatic substitution (SNAr) was developed as the final step in an improved manufacturing process to belzutifan. The reaction performed water enable a reactive crystallization and direct isolation of drug substance toward green sustainable process. Due sensitivity vapor phase composition, engineering controls around headspace pressure sweep rate were tuned balance reactivity selectivity maximize product yield purity. Ultimately, our investigation resulted robust process, which successfully demonstrated at pilot plant scale.
Language: Английский
Citations
4
Organic Letters, Journal Year: 2024, Volume and Issue: 26(19), P. 4059 - 4064
Published: May 6, 2024
Herein, we report a nine-step synthesis of belzutifan enabled by novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, final ketone reduction in proceeds diastereoselectivity, leading expedient assembly stereotriad. In contrast original 16-step synthesis, this route avoids lengthy bromination–oxidation sequence and introduces sulfone functionality via nucleophilic aromatic substitution, obviating need for transition metal catalysis.
Language: Английский
Citations
1
Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(13)
Published: Jan. 27, 2024
Abstract Biocatalytic oxidations are an emerging technology for selective C−H bond activation. While promising a range of oxidations, practical use enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering application non‐heme iron α‐ketoglutarate‐dependent dioxygenase direct stereo‐ regio‐selective non‐native fluoroindanone en route to oncology treatment belzutifan, replacing five‐step chemical synthesis with enantioselective hydroxylation. Mechanistic studies indicated that formation desired product was enzyme overoxidation, these properties subsequently improved directed evolution, yielding biocatalyst capable >15,000 total turnovers. Highlighting industrial utility this biocatalyst, high‐yielding, green, efficient oxidation demonstrated at kilogram scale belzutifan.
Language: Английский
Citations
0
Published: May 3, 2024
Language: Английский
Citations
0
Reaction Chemistry & Engineering, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 18, 2024
A generalizable active learning framework enables accurate prediction of mass transfer coefficients ( k L a ), and iterative design experiments to efficiently characterize new reactor configurations with minimal experimental trials.
Language: Английский
Citations
0