Evaluation and Screening of Spherical Pd/C for Use as a Catalyst in Pharmaceutical-Scale Continuous Hydrogenations

Fernandez-Puertas, Eneritz; Robinson, Andrew; Robinson, Hannah L; Sathiyalingam, Shainthavaan; Stubbs, Heather; Edwards, Lee J.

doi:10.1021/acs.oprd.0c00183

Cited by 20 publications

(34 citation statements)

References 54 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To solve the chemical compatibility issue, we turned our attention to Pd-CSMs, which are 3D-printed from chemically resistant stainless steel 316L . The nitro reduction was operated at the platform’s upper limit of 120 °C to suppress catalyst deactivation. , When we experimentally evaluated two Pd-CSMs in series with 2c starting material (Table , entries 3–4), the stainless steel scaffold was indeed chemically resistant to the DIPEA·HF byproduct, but deactivation was eventually observed after a few hours of operation. An attempt to regenerate the Pd catalyst in situ , did not restore the original catalyst activity (Figure C(a)).…”

Section: Resultsmentioning

confidence: 99%

“…Two FT-IR modules were deployed to monitor both the activation reaction and the nitro reduction Pd catalyst stability in real-time over the course of the campaign. A spherical Pd 0 /C catalyst (Heraeus GmbH) with high surface area (see SI) and low pressure drop was used for the nitro reduction, which was operated at high temperature (125 °C) to minimize the likelihood of deactivation. The overall yield of sonidegib 6 was determined via an LC-MS module after the amide coupling reactor.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Bayesian Optimization of Computer-Proposed Multistep Synthetic Routes on an Automated Robotic Flow Platform

et al. 2022

View full text Add to dashboard Cite

Computer-aided synthesis planning (CASP) tools can propose retrosynthetic pathways and forward reaction conditions for the synthesis of organic compounds, but the limited availability of context-specific data currently necessitates experimental development to fully specify process details. We plan and optimize a CASP-proposed and human-refined multistep synthesis route toward an exemplary small molecule, sonidegib, on a modular, robotic flow synthesis platform with integrated process analytical technology (PAT) for data-rich experimentation. Human insights address catalyst deactivation and improve yield by strategic choices of order of addition. Multi-objective Bayesian optimization identifies optimal values for categorical and continuous process variables in the multistep route involving 3 reactions (including heterogeneous hydrogenation) and 1 separation. The platform's modularity, robotic reconfigurability, and flexibility for convergent synthesis are shown to be essential for allowing variation of downstream residence time in multistep flow processes and controlling the order of addition to minimize undesired reactivity. Overall, the work demonstrates how automation, machine learning, and robotics enhance manual experimentation through assistance with idea generation, experimental design, execution, and optimization.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Bayesian Optimization of Computer-Proposed Multistep Synthetic Routes on an Automated Robotic Flow Platform

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Trickle bed hydrogenation has been used in other industries for decades , and in recent years has been gradually adopted by the pharmaceutical industry. − Considering the intrinsic process safety hazard associated with the use of H 2 on a large scale and the flammability of Pd(OH) 2 /C, it is logical to extend continuous processing to the hydrogenation step.…”

Section: Results and Discussionmentioning

confidence: 99%

Developing a Multistep Continuous Manufacturing Process for (1R,2R)-2-Amino-1-methylcyclopentan-1-ol

Duan

Feng²,

Gonzalez³

et al. 2020

Org. Process Res. Dev.

View full text Add to dashboard Cite

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.

show abstract

“…To examine the continuousflow applicability of the hydrogenation step of INT12, first we applied reaction conditions similar to our original batch technology, utilizing a hydrogen cylinder and an HM150 heterogeneous flow reactor system manufactured by H-ION Ltd. (Hungary). 32 This reactor is equipped with two liquid/gas inlets, a T-mixer, chargeable columns of various sizes (80−250 mm lengths, 4 mm inner diameter), a BPR unit, and a quenchinlet for addition of further reagents. The equipment can operate at up to 150 °C, 100 bar, and ca.…”

Section: Flow Hydrogenationmentioning

confidence: 99%

Development and Process Intensification of an Efficient Flow–Cascade Reaction Sequence in the Synthesis of Afizagabar

Pethő

Szilágyi

Mengyel

et al. 2022

Org. Process Res. Dev.

View full text Add to dashboard Cite

Aromatic nitration and catalytic hydrogenation are among the most dangerous reactions in the chemical industry. The traditional, batchwise pilot plant manufacturing process of a key intermediate of our drug candidate afizagabar (S44819) involved these kinds of transformations (besides a Dakin−West-type reaction, a ring closure, and a keto reduction step). To mitigate some of the hazards associated with this sequence, a flow chemical approach was developed. First, a flow−cascade process was elaborated, which furnished the product with a throughput of 1.52 g/h with an HPLC purity of 95.6%. The bottleneck of the procedure in terms of output was the heterogeneous catalytic hydrogenation; therefore, our subsequent process intensification efforts primarily concentrated on this step. Finally, application of higher concentrations and an upscaled hydrogenation reactor combined with the corresponding adjustment of parameters of further reaction steps resulted in an efficient process with an effective product yield of 11.95 g/h and an increased HPLC purity (97.1%). The 4-step uninterrupted process described here is based on a newly developed heterogeneous flow reactor system and a custom-made liquid−liquid extractor, providing an instructive case study on handling hazardous processes in a safe and efficient way.

show abstract

Evaluation and Screening of Spherical Pd/C for Use as a Catalyst in Pharmaceutical-Scale Continuous Hydrogenations

Cited by 20 publications

References 54 publications

Bayesian Optimization of Computer-Proposed Multistep Synthetic Routes on an Automated Robotic Flow Platform

Bayesian Optimization of Computer-Proposed Multistep Synthetic Routes on an Automated Robotic Flow Platform

Developing a Multistep Continuous Manufacturing Process for (1R,2R)-2-Amino-1-methylcyclopentan-1-ol

Development and Process Intensification of an Efficient Flow–Cascade Reaction Sequence in the Synthesis of Afizagabar

Contact Info

Product

Resources

About