Organic Process Research & Development最新文献

An efficient, scalable, and safe synthesis of 1-(2,2,2-trifluoroethyl)cyclopropane-1-carboxylic acid (compound 1) was developed, starting from the inexpensive and readily available trifluoro-iodopropane 18. This was accomplished through detailed optimization of the conditions for the key Simmons–Smith cyclopropanation reaction. The optimized process was used to prepare multi-kilograms of this intermediate, supporting early development activities of a pharmaceutical candidate.

Dorzolamide hydrochloride is a topical carbonic anhydrase (CA) inhibitor that controls elevated intraocular pressure (IOP) associated with open-angle glaucoma and ocular hypertension. An improved commercial-scale synthesis of dorzolamide was developed to overcome the limitations of previously reported methods in terms of yield, cost, and scalability. A key step in this scheme is the highly stereoselective early-stage epimerization followed by recrystallization-based purification of the key intermediate by using a unique solvent system. The optimized synthetic process exhibited robustness in the batch manufacturing of dorzolamide, consistently delivering a 70% overall yield and meeting quality specifications in line with the ICH guidelines. Alternatively, a new synthetic route for dorzolamide hydrochloride has been developed, employing trimethyl orthoacetate and benzylsulfonyl chloride, which features an enantioselective reaction that results in improved yield and purity.

We report the development and scale-up of a first-generation route to PF-07293893, an AMPKγ3 activator for the treatment of heart failure. The synthesis includes a metal-catalyzed C–N coupling, a telescoped N-Boc deprotection/amidation sequence, and a final recrystallization. Strategic process optimization addressed key challenges, such as reaction stalling, metal removal, and intermediate instability, ultimately enabling the delivery of over 7.5 kg of API for regulatory toxicological and phase 1 clinical studies.

A commercial-scale synthesis process for 3-fluoro-4-(hydroxymethyl)benzonitrile (1), a key compound in the production of danuglipron, has been developed to support clinical and commercial demands. Early development efforts explored multiple synthetic routes, identifying several that were suitable for scale-up and resulting in the production of over one metric ton of the compound. The optimized commercial process for 1 features a radical photobromination as a pivotal step followed by selective hydrolysis, achieving an overall yield of 77%.

The transformation of carboxylic acids to their corresponding aldehydes is one of the most important reactions in both organic syntheses and industrial applications. Our previous research reported an efficient and convenient aldehyde preparative method via controllable reduction of carboxylic acids with pinacolborane (HBpin/DMAP). However, the new method still suffered from some limitations during scaling-up, for example, a large excess of reagents, obvious exotherms, and silica gel column purification. The process development was performed to address these troublesome issues and also to make the new method a practical synthetic protocol. After the detailed exploration of reaction parameters, including the reaction conditions, charging mode, and workup methods, a safe, efficient, and column-free process of reduction of aromatic carboxylic acids to aldehydes via DMAP/HBpin has been successfully established. The newly developed robust process could provide a practical and alternative method for straightforward access of aldehydes from carboxylic acids.

Thermal runaway from chemical reactions is the result of competition between heat generation and heat dissipation in industrial chemical vessels. However, the worldwide used T_D24 (the temperature at which time to maximum rate under adiabatic conditions equals 24 h) focuses solely on heat generation for abnormal conditions of cooling failure, which account for only an insignificant portion of thermal runaway incidents. In contrast, the temperature of no return (TNR), defined by the balance of heat generation and heat dissipation, provides a more relevant threshold for process upsets in industrial chemical vessels. As the operating temperature approaches the TNR, minor thermal disturbances can precipitate thermal runaway. To estimate this threshold, calorimetry is coupled with reactor-scale energy-balance modeling. Kinetic parameters are determined using accelerating rate calorimetry (ARC), with corroborating measurements from differential scanning calorimetry (DSC), vent sizing package (VSP) calorimetry, and micro reaction calorimetry (μRC). In this work, the downside of T_D24 for runaway hazard assessment is first analyzed. Guided by the Semenov diagram, a heat-balance model for stirred-tank reactors (STRs) is established, and based on ARC tests on a 20 wt % solution of di-tert-butyl peroxide (DTBP) in toluene under adiabatic conditions, a heat-generation-rate expression and a coolant heat-dissipation-rate expression are derived. A computational procedure is then proposed to determine TNR. Relative to adiabatic T_D24, TNR supports optimization of reactor-cooling design, enhancing alarms and interventions under abnormal conditions, and quantitative assessment of reaction hazards.