查看更多>>摘要：When multiobjective particle engineering is needed,an extensive array of crystallization process development tools are necessary.An example of such an endeavor was reported by a team from Loughborough University and Takeda Pharmaceuticals(Sun,Z.;et al.Cryst.Growth Des.,DOI:10.1021/acs.cgd.lc01510).Compound X(a Takeda API) can crystallize as stable form A(desired) or as metastable form L exhibiting heavy agglomeration.A cooling antisolvent crystallization process was developed using solubility data and optimization of the solute concentration,antisolvent-cooling sequence,cooling protocol,seed amount(9.8-23.8%),and location.Process analytical technology(PAT) tools included calibrated UV-vis spectroscopy and focused-beam reflectance measurement(FBRM).Even though improvements in particle size and shape were observed,the specifications were not met,and wet milling was also employed.To remove the undesired fines obtained during wet milling,temperature cycling was included in the process,first in an open loop and then,for better results,in a closed feedback loop of direct nucleation control(DNC) using a target FBRM particle count.Utilizing suitable automated lab reactors,DNC allows for automated manipulation of heating/cooling and solvent/antisolvent addition.The API thus produced met specifications,showing a much lower degree of agglomeration than in the original process.
查看更多>>摘要：The American Chemical Society(ACS) Green Chemistry Institute(GCI) Pharmaceutical Roundtable(PR) was developed in 2005 to encourage the integration of green chemistry and green engineering into the pharmaceutical industry.The ACS GCI is a not-for-profit organization whose mission is to catalyze and enable the implementation of green and sustainable chemistry throughout the global chemistry enterprise.The ACS GCI PR is composed of pharmaceutical and biotechnology companies,including contract research/manufacturing organizations and generic pharmaceuticals.For details of the current membership,see acsgcipr.org.
查看更多>>摘要：Within this edition of regulatory highlights,we focus on two specific areas.First,a reflection on the status relating to investigation into N-Nitrosamines;and current,growing concerns.Second,we explore the Publication of version 1 of the EMA PRIME Quality toolbox and how this can assist in terms of earlier access to new medicines.
查看更多>>摘要：An emerging interest for the application of periodate in the synthesis of active pharmaceutical ingredients(APIs) and for the valorization of renewable feedstock is eminent.However,periodate exhibits a high molecular mass,is expensive compared to other common bulk-oxidizers and is used only reluctantly in technical applications.Recently,a new and green electrochemical synthesis was established.The preparation and regeneration method for periodate lowers costs and enables the use of periodate in the synthesis of regulated products.This review will briefly introduce the key innovations in the electrochemical synthesis of periodate and will survey the most important applications of periodate in the production of fine chemicals.
查看更多>>摘要：Five-membered cyclic sulfamidates are very valuable electrophiles in organic synthesis and readily used on a multikilogram scale.However,their thermal degradation is underreported and might lead to unforeseen and undesirable safety events.In addition,ring or nitrogen substitution can have a tremendous influence on cyclic sulfamidate reactivity toward bases and therefore impact the overall safety assessment of a process.An understanding of such behavior is therefore of high importance in the industry while designing a synthetic route,as a change of,e.g.,a protecting group can increase the thermal safety of a step on scale.We report herein the thermal degradation investigation as well as the structure-related reactivity exploration of cyclic sulfamidates,including their use in combination with strong bases.The design of a predictive model to rapidly assess the thermal hazard based on collected data and selected molecular descriptors is also presented.
查看更多>>摘要：Before scaling up to production,it is of high importance to evaluate the potential of a reaction to lead to an undesired thermal degradation event.The use of a large amount of compounds is usually required for a reliable calorimetry study.In this work,we report the development of a milliliter-scale reaction calorimeter for reaction screening applications.The setup was designed using laboratory equipment and characterized and validated with routine experiments.The results were sufficiently accurate enabling us to observe trends in the measured reaction enthalpies of a family of compounds reacting with strong bases as a function of the compounds'structures..The use of the microscale tailor-made calorimeter is considered very valuable for potentially highly energetic reactions since reaction calorimetry studies can be performed accurately and safely with small amounts of valuable materials.
查看更多>>摘要：Described herein is the discovery and development of a process to prepare an atropisomeric intermediate in the synthesis of the KRAS G12C inhibitor sotorasib.Using high-throughput experimentation,(+)-2,3-dibenzoyl-D-tartaric acid[(+)-DBTA]was identified as an inexpensive and readily available resolving agent that enables separation and isolation of the desired atropisomer through a classical resolution.Subsequent optimization and characterization studies led to a highly selective process,providing the desired atropisomer as a unique three-component cocrystal solvate with a selectivity of>2000;1.This classical resolution has been performed successfully on>500 kg scale and was critical to the commercialization of the sotorasib manufacturing process.
查看更多>>摘要：The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described.Part 1 of this two-part series details the design and execution of a classical resolution to generate atropisomer M-l from a racemic precursor(rac-l).In parallel,the team sought to develop a racemization process to enable recycling of the classical resolution waste stream and maximize productivity and sustainability.Computational and experimental methods revealed a high barrier to rotation(ca.42 kcal/mol) prompting the design of a high-temperature(>300 ℃) racemization protocol for recovery of the racemic compound.Described herein are the determination of the barrier to rotation,optimization of conditions to enable racemization,proof-of-concept for a continuous-flow process to execute the process,and kilogram-scale demonstration,including(1) recovery of the undesired atropisomer as a crystalline solid from the classical resolution waste stream,(2) thermal racemization by a high-temperature continuous-flow process,and(3) isolation of the racemic compound by crystallization directly from the reaction stream.
查看更多>>摘要：In this article,an improved synthesis of a key triazole intermediate in the synthesis of bromo-and extra-terminal domain(BET) inhibitor GSK525762(1) is described,which avoids the need for the formation of a thioamide intermediate for the key methyltriazolo[1,4]benzodiazapine formation.Conditions for a phosphorylative activation of lactam 4 were identified through the extensive screening of reagents and solvents,where a number of phosphazene bases were found to have unmatched activity.Development efforts focused on the use of phosphazene base Pl-t-Bu-tris(tetramethylene)(BTPP) with diethyl chlorophosphoridate(DECP) and culminated in the demonstration of the new process at a 750 g scale.The resulting synthetic route avoids the use of thiolating agent P255 and isolation of the resulting thioamide while delivering 1 in exceptional purity with a reduced number of steps,resulting in a higher yield and improved throughput over the previous process.
查看更多>>摘要：In this paper,an expeditious and efficient continuous-flow process is reported for the synthesis of syn-2-amino-,3-diol.The starting material syn-2-nitro-1,3-diol reacts with hydrogen gas in a micro fixed-bed reactor packed with a Raney Ni catalyst to provide syn-2-amino-1,3-diol in 93% isolated yield.The reaction time in the flow system was markedly reduced(from 36 h in batch to 5 min in flow) due to enhanced mass transfer.The effects of the catalyst,solvent,reaction temperature,reaction time,pressure,and H2 flow rate have been investigated successively.The optimum conditions for the continuous-flow reaction are described as follows when using Raney Ni as a catalyst at a reaction temperature of 25 ℃,a reaction pressure of 10 bar,a reaction solvent of 3% AcOH in methanol,an H2 flow rate of 25 sccm,and a liquid flow rate of 0.6 mL/min.The reaction kinetics in the temperature range of 10-40 ℃ were investigated.The reaction rate constants and activation energy were determined.The continuous flow system allows for an efficient hydrogenation of syn-2-nitro-1,3-diol on the hectogram scale,corresponding to an overall productivity of 73.6 g/d after continuous operation for over 240 h.
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