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  • 2020

    Development and Proof of Concept for a Large-Scale Photoredox Additive-Free Minisci Reaction

    Mark A. Graham*, Gary Noonan*, Janette H. Cherryman, James J. Douglas, Miguel Gonzalez, Lucinda V. Jackson, Kevin Leslie, Zhi-qing Liu, David McKinney, Rachel H. Munday, Chris D. Parsons, David T. E. Whittaker, En-xuan Zhang, and Jun-wang Zhang

    Org. Process Res. Dev.  2021, 25, 1, 57–67

    Publication Date: December 15, 2020


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    New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern–Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proof-of-concept data for the future application of this technology in the clinical manufacture of ceralasertib.

  • Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib

    Mark A. Graham*, Hannah Askey, Andrew D. Campbell, Lai Chan, Katie G. Cooper, Zhaoshan Cui, Andrew Dalgleish, David Dave, Gareth Ensor, Rita Galan, Peter Hamilton, Claire Heffernan, Lucinda V. Jackson, Dajiang Jing, Martin F. Jones, Pengpeng Liu, Keith R. Mulholland, Mohammed Pervez, Michael Popadynec, Emma Randles, Simone Tomasi, and Shenghua Wang

    Org. Process Res. Dev.  2021, 25, 1, 43–56

    Publication Date: December 15, 2020


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    Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An SNAr reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer–Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.

  • Electroreductive Olefin–Ketone Coupling

    Pengfei Hupengfei Hu, Byron K. Peters, Christian A. Malapit, Julien C. Vantourout, Pan Wang, Jinjun Li, Lucas Mele, Pierre-Georges Echeverria, Shelley D. Minteer*, And Phil S. Baran*


    J. Am. Chem. Soc. 2020, 142, 50, 20979–20986
    Publication Date: December 1, 2020


    展开

    Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An SNAr reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer–Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.

  • Semicontinuous Process for GMP Manufacture of a Carbapenem Intermediate via Carbene Insertion Using an Immobilized Rhodium Catalyst

    James R. Gage*, Furong Chen, Changming Dong, Miguel A. Gonzalez, Yong Jiang, Yong Luo, Mark D. McLaws, and Jian Tao

    Org. Process Res. Dev. 2020, 2020, 24, 10, 2025–2033

    Publication Date: June 15, 2020


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    A two-stage flow process for cGMP manufacture of a commercially important carbapenem intermediate was developed. Stage 1 featured an intramolecular N–H insertion reaction catalyzed by an immobilized rhodium catalyst. In stage 2, phosphorylation of the resulting keto ester intermediate afforded the target, which was isolated in batch mode. The equipment design and process control strategy leading to validation of the process at the 100 kg scale are discussed.


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  • Development and Execution of a Production-Scale Continuous [2+2] Photocycloaddition

    M. G. Beaver,* E. Zhang, * Z. Liu, S. Zheng, B. Wang, J. Lu, J. Tao, M. Gonzalez, S. Jones, J. S. Tedrow

    Org. Process Res. Dev. 2020, 24, 10, 2139–2146

    Publication Date:May 27, 2020


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    This article details the approach to large-scale production of cyclobutane 2 by the continuous-flow [2 + 2] photocycloaddition of maleic anhydride and ethylene, including (1) focused reaction optimization and development of a robust isolation protocol, (2) the approach to equipment design and process safety, and (3) the results of commissioning tests and production runs delivering the target compound at throughputs exceeding 5 kg/day.


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  • Synthesis, Optimization, and Large-Scale Preparation of the LowDose Central Nervous System-Penetrant BACE1 Inhibitor LY3202626 via a [3 + 2] Nitrone C

    P. Garcia-Losada,* A. C. DeBaillie, J. E. Diego, S. J. Green, M. M. Hansen, C. Jaramillo, M. Johnson, T. Kaoudi, J. Li, P. J. Lindsay-Scott, C. Mateos, D.J. Mergott, J. A. Rincon, R.R. Rothhaar, K. D. Seibert, B. M. Watson, L. L. Winneroski, S. Gangula, D. Jing, H. Sun, L. Zhang, and M. O. Frederick,*
    Org. Process Res. Dev. 2020, 24, 306?314

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    Herein we report a summary of the synthetic development of LY3202626 from the initial discovery route to a final route that was scaled to make 150 kg. Key developments include the use of a [3 + 2] cyclization to set the cis ring junction of the formed isoxazoline, a one-pot thiazine formation, and three different ways to install the aniline: (1) Cu-catalyzed azide coupling and reduction, (2) nitration and reduction, and (3) Buchwald coupling with acetamide.


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  • 2019

    The PMI Predictor app to enable green-by-design chemical synthesis

    Borovika, Alina; Albrecht, Jacob; Li, Jun; Wells, Andrew S.; Briddell, Christiana; Dillon, Barry R.; Diorazio, Louis J.; Gage, James R.; Gallou, Fabrice; Koenig, Stefan G.; et al
    Nat Sustain 2, 1034–1040 (2019)

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    The development of sustainable processes for the synthesis of new clinical candidates is a priority for every pharmaceutical company. The ultimate efficiency of a molecule’s synthesis results from a combination of the sequence of steps to assemble the molecule and the efficiency of each of the steps. While multiple approaches are available to aid the development of efficient processes, far fewer methods to guide route innovation have been described. Here we present a ‘green-by-design’ approach to route selection and development, assisted by predictive analytics and historical data. To aid the selection of more efficient strategies, we created a user-friendly web application, the ‘PMI Predictor’ (accessible from https://acsgcipr-predictpmi.shinyapps.io/pmi_calculator/), to predict the probable efficiencies of proposed synthetic routes before their evaluation in the laboratory. We expect that use of this app will bring greater awareness of sustainability during the initial phase of route design and will contribute to a reduced environmental impact of pharmaceutical production.

  • Identification of an Oxalamide Ligand for Copper-Catalyzed C–O Couplings from a Pharmaceutical Compound Library

    V. S. Chan, S. W. Krabbe, C. Li, L. Sun, Y. Liu, A. J. Nett
    ChemCatChem, 2019, 11, 5748-5753

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    A simple and robust method for electrochemical alkyl C–H fluorination is presented. Using a simple nitrate additive, a widely available fluorine source (Selectfluor), and carbon-based electrodes, a wide variety of activated and unactivated C–H bonds are converted into their C–F congeners. The scalability of the reaction is also demonstrated with a 100 gram preparation of fluorovaline.


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  • Electrochemical C(sp3)–H Fluorination

    Takahira, M. Chen, Y. Kawamata, P. Mykhailiuk, H. Nakamura, B. K. Peters, S. H. Reisberg, C. Li, L. Chen, T. Hoshikawa, T. Shibuguchi, P. S. Baran
    Synlett, 2019, 30,1178-1182

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    A simple and robust method for electrochemical alkyl C–H fluorination is presented. Using a simple nitrate additive, a widely available fluorine source (Selectfluor), and carbon-based electrodes, a wide variety of activated and unactivated C–H bonds are converted into their C–F congeners. The scalability of the reaction is also demonstrated with a 100 gram preparation of fluorovaline.


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  • Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications

    Kawamata, J. C. Vantourout, D. P. Hickey, P. Bai,L. Chen, Q. Hou, W. Qiao, K. Barman, M. A. Edwards, A. F. G.-C., J. N. deGruyter, H. Nakamura, K.W. Knouse, C. Qin, K. J. Clay, D. Bao, C. Li, J. T. Starr, C. G. Irizarry, N. Sach, H. S. White, M. Neurock, S. D. M., P. S. Baran
    J. Am. Chem. Soc., 2019, 141,6392-6402

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    C–N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.


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  • Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry

    K. Peters, K. X. Rodriguez, S. H. Reisberg, S. B. Beil, D. P. Hickey, Y. Kawamata, M. Collins, J. Starr, L. Chen, S. Udyavara, K. Klunder, T. J. Gorey, S. L. Anderson, M. Neurock, S. D. Minteer, P. S. Baran
    Science, 2019, 363, 838-845

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    Reductive electrosynthesis has faced long-standing challenges in applications to complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology [tris(pyrrolidino)phosphoramide] can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemical conditions can be applied to other dissolving metal–type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings.


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  • 2018

    Continuous Production of Anhydrous tert-Butyl Hydroperoxide in Nonane Using Membrane Pervaporation and Its Application in Flow Oxidation of a γ‑Butyro

    Bryan Li Steven M. Guinness, Steve Hoagland, Michael Fichtner, Hui Kim, Shelly Li, Robert J. Maguire, J. Christopher McWilliams, Jason Mustakis, Jeffrey Raggon, Dan Campos, Chris. R. Voss, Evan Sohodski Bryan Feyock, Hannah Murnen, Miguel Gonzalez, Matthew Johnson, Jiangping Lu, Xichun Feng, Xingfang Sun, Songyuan Zheng, and Baolin Wu
    Org. Process Res. Dev. 2018, 22, 707-720

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    Anhydrous tert-butyl hydroperoxide (TBHP) is a powerful oxidizing agent in many chemical transformations. Despite the versatility in organic reactions, the use of anhydrous TBHP has been greatly limited because of safety concerns over its shipping, handling, and storage, particularly on production scale. Herein we describe a membrane pervaporation method that allows the production of the anhydrous TBHP solution in continuous manner. The system consists of membrane modules in series that are made of perfluorinated polymer with very high gas permeability, allowing it to remove water efficiently. The pervaporation skid has been successfully implemented in production by continuously generating anhydrous 1.5 M TBHP solution in nonane at a rate of up to 100 mL·min–1 for more than 96 h, achieving the target of 0.15 wt % water. An integrated flow oxidation of a γ-butyrolactam substrate provides an efficient and diastereoselective synthesis of a key lactam intermediate for the preparation of a drug candidate targeting interleukin-1 receptor associated kinase 4 for the treatment of inflammation and oncology diseases.


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  • Kinetically guided radical-based synthesis of C(sp3)−C(sp3) linkages on DNA

    Wang, H. Lundberga, S. Asaia, P. Martín-Acostaa, J. S. Chena, S. Brownb, W. Farrellc, R.G. Dushin, C. J. O’Donnell, A. S. Ratnayakeb, P.  Richardsonc, Z. Liu, T. Qin, D. G. Blackmond, P. S. Barana
    Proc. Natl. Acad. Sci., 2018, 115, E6404-E6410

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    DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp3)?C(sp3) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C–C bonds on DNA was studied, which represents a radical-based synthesis in DEL.


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  • Modular radical cross-coupling with sulfones enables access to sp3-rich (fluoro)alkylated scaffolds

    R.R. Merchant, J. T. Edwards, T. Qin, M. M. Kruszyk, C. Bi,G. Che, D. Bao, W. Qiao L. Sun, M. R. Collins, O. O. Fadeyi, G. M. Gallego, J. J. Mousseau, P. Nuhant, P. S. Baran
    Science, 2018, 360,75-80

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    Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron–induced variants of this reaction class have proven particularly useful in the formation of C(sp2 )–C(sp3 ) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method’s tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.


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  • A General Protocol for Addressing Speciation of the Active Catalyst Applied to Ligand-Accelerated Enantioselective C(sp3)−H Bond Arylation

    E. Hill, Q. Pei, E. Zhang, J. R. Gage, J. Yu, D. G. Blackmond
    ACS Catal. 2018, 8, 1528-1531

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    The potential role of dimeric catalyst species on or off the catalytic cycle is considered for a case of Pd-catalyzed C–H functionalization, leading to the development of a general experimental protocol that uses the reaction itself to report on the presence and role of dimeric species in asymmetric catalytic reactions.


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  • 2017

    CITU: A Peptide and Decarboxylative Coupling Reagent

    J.N. deGruyter, L. R. Malins, L. Wimmer, K. J. Clay, J. Lopez-Ogalla, T. Qin, J. Cornella, Z. Liu, G. Che, D. Bao, J. M. Stevens, J. X. Qiao, M. P. Allen, M. A. Poss, P. S. Baran
    Org. Lett. 2017, 19, 6196-6199

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    Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations.


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  • An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary

    Pei, G. Che,R. Zhu, J.He, J. Yu
    Org. Lett. 2017, 19, 5860-5863

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    A practical method for the removal of a versatile acidic amide auxiliary has been developed. Facile alcoholysis of the amide in the presence of KOAc is enabled by an epoxide, which mechanistically resembles the removal of the Myers’ auxiliary. The protocol has been applied to the removal of a variety of amide substrates and their C–H functionalization products with high efficiency and low cost, representing a step forward toward the development of a versatile directing group for C–H activation.


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  • Electrochemically Enabled, Ni-Catalyzed Amination

    Li, Y. Kawamata, H. Nakamura, J. C. Vantourout, Z. Liu, Q. Hou, D. Bao, J.T. Starr, J.Chen, M. Yan, P.S. Baran
    Angew. Chem. Int. Ed., 2017, 56, 13088-13093

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    Along with amide bond formation, Suzuki cross‐coupling, and reductive amination, the Buchwald–Hartwig–Ullmann‐type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional‐group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar?Cl, Ar?Br, Ar?I, Ar?OTf), amine types (primary and secondary), and even alternative X?H donors (alcohols and amides).


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  • Decarboxylative Alkynylation

    M. Smith, T. Qin, R. R. Merchant, J. T. Edwards, L. R. Malins,Z. Liu, G. Che, Z. Shen, S. A. Shaw, M. D. Eastgate, P. S. Baran*
    Angew. Chem. Int. Ed., 2017, 56, 11906-11910

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    The development of a new decarboxylative cross‐coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel‐ and iron‐based catalysts. The use of N‐hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in?situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well‐established alkyne syntheses. The reaction is operationally simple and broad in scope while providing succinct and scalable avenues to previously reported synthetic intermediates.


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  • Coupling of Challenging Heteroaryl Halides with Alkyl Halides via Nickel-Catalyzed Cross-Electrophile Coupling

    Hansen*, C. Li, S. Yang, D. Pedro, D. Weix*
    J. Org, Chem., 2017, 82, 7085-7694

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    Despite their importance, the synthesis of alkylated heterocycles from the cross-coupling of Lewis basic nitrogen heteroaryl halides with alkyl halides remains a challenge. We report here a general solution to this challenge enabled by a new collection of ligands based around 2-pyridyl-N-cyanocarboxamidine and 2-pyridylcarboxamidine cores. Both primary and secondary alkyl halides can be coupled with 2-, 3-, and 4-pyridyl halides as well as other more complex heterocycles in generally good yields (41 examples, 69% ave yield).


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  • Scalable, Electrochemical Oxidation of Unactivated C−H Bonds

    Kawamata, M. Yan, Z. Liu,D. Bao, J. Chen, J. T. Starr, P. S. Baran*
    J. Am. Chem. Soc.,2017, 139, 7448–7451

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    A practical electrochemical oxidation of unactivated C–H bonds is presented. This reaction utilizes a simple redox mediator, quinuclidine, with inexpensive carbon and nickel electrodes to selectively functionalize “deep-seated” methylene and methine moieties. The process exhibits a broad scope and good functional group compatibility. The scalability, as illustrated by a 50 g scale oxidation of sclareolide, bodes well for immediate and widespread adoption.


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  • Decarboxylative Alkenylation

    T. Edwards, R. R. Merchant, K. S. McClymont, K. W. Knouse, T. Qin, L. R. Malins, B. Vokits, S. A. Shaw,D.Bao, F. Wei, T. Zhou, M. D. Eastgate, P. S. Baran*
    Nature, 2017, 545,213-218

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    Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.


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  • 2016

    Chemoselective Synthesis of Polysubstituted Pyridines from Heteroaryl Fluorosulfates

    Zhang*, J. Tang, S. Li, P. Wu, J. E. Moses, K. B. Sharpless*
    Chem. Eur. J, 2016, 22, 5692 – 5697

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    A selection of heteroaryl fluorosulfates were readily synthesized using commercial SO2F2 gas. These substrates are highly efficient coupling partners in the Suzuki reaction. Through judicious selection of Pd catalysts the fluorosulfate functionality is differentiated from bromide and chloride; the order of reactivity being: ‐Br> ‐OSO2F> ‐Cl. Exploiting this trend allowed the stepwise chemoselective synthesis of a number of polysubstituted pyridines, including the drug Etoricoxib.


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  • Scalable and sustainable electrochemical allylic C-H oxidation

    J. Horn, B. R. Rose, Y. Chen, J. Tang, K. Chen, M. D. Eastgate, P. S. Baran*
    Nature, 2016, 533, 78-81

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    New methods and strategies for the direct functionalization of C–H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials1. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C–H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials2. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as “classics”3. Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium)2. These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C–H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C–H oxidation (demonstrated on 100?grams), enabling the adoption of this C–H oxidation strategy in large-scale industrial settings without substantial environmental impact.


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  • 2012

    High Output Continuous Nitration

    J. R. Gage,*X. Guo, J.Tao, C. Zheng
    Org. Process Res. Dev. 2012, 16, 930-933

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    The design and use of a flow reactor for scaling up an exothermic nitration reaction in a safe manner on production scale is described. The flow reactor is made of a jacketed, stainless steel coil. Two charging methods, pump and nitrogen pressure were tested on a substituted pyridine substrate. The transfer from kilogram scale in the laboratory to 100-kg scale in the plant was successfully accomplished.


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  • 邮编:300457
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  • 传真:022-66252777
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