Bing-Shiou Yang - Academia.edu (original) (raw)

Papers by Bing-Shiou Yang

Research paper thumbnail of Efficient Iron-Catalyzed Kumada Cross-Coupling Reactions Utilizing Flow Technology under Low Catalyst Loadings

European Journal of Organic Chemistry, Apr 19, 2016

An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling ... more An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents in presence of low catalyst loadings (0.5 mol-%). Compared to batch mode, the continuous flow approach overcomes the exothermicity which enabled longer catalyst lifetime, facilitated scale-up and signifi-[a] Chemical Development,

Research paper thumbnail of Automated Reactions in Continuous Flow Reactors

Research paper thumbnail of ChemInform Abstract: Efficient Iron-Catalyzed Kumada Cross-Coupling Reactions Utilizing Flow Technology under Low Catalyst Loadings

ChemInform, Sep 1, 2016

Polyphenylalkane derivatives Q 0720 Efficient Iron-Catalyzed Sakurai-Michael Addition of Allyltri... more Polyphenylalkane derivatives Q 0720 Efficient Iron-Catalyzed Sakurai-Michael Addition of Allyltrimethylsilane to Chalcones.-The chemoselective reaction is catalyzed by the combination of iron(III) salts and TmsCl.

Research paper thumbnail of Bioavailability-Enhancing Cocrystals: Screening, <i>In Vivo</i> Predictive Dissolution, and Supersaturation Maintenance

Crystal Growth & Design, Aug 16, 2022

Research paper thumbnail of Development of a Practical Process for the Synthesis of PDE4 Inhibitors

Organic Process Research & Development, May 5, 2016

A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inh... more A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inhibitors represented by 1 and 2 was developed and demonstrated on a multi-kilogram scale. Key aspects of the process include the regioselective synthesis of dihydrothieno[3,2-d]pyrimidine-2,4-diol 9 and the asymmetric sulfur oxidation of intermediate 11.

Research paper thumbnail of Diverse Solvent Selection for Polymorph Landscape Investigation Based on Specific API–Solvent Interactions

Crystal Growth & Design, Feb 19, 2020

Selection of a diverse set of solvents is important for systematic investigation of polymorph lan... more Selection of a diverse set of solvents is important for systematic investigation of polymorph landscape and quick identification of the stable polymorph. The diversity of selected solvents is usually defined by solvent properties only, such as solvent functional groups, polarity, and hydrogen bonding capabilities. It is desired to customize solvent selection based on API (active pharmaceutical ingredients) molecular structures, especially API-solvent interactions related to crystallization behaviors. In this study, the crystallization related API-solvent interactions were profiled using the relative conformer distributions in solutions, which was visualized as conformer solvent maps to guide solvent selection for polymorph landscape investigation. Quantum mechanics and COSMO-SAC methods were utilized to calculate the relative distributions of representative conformers of API molecules in solutions. Interplay between relative conformer distribution and API molecular cluster in solution were studied using molecular dynamics, where virtual supersaturated solutions were simulated using large numbers of API and solvent molecules. The results suggested that relative conformer distribution could influence the structure of API molecular clusters and subsequent crystallization processes. Systematically varying the relative conformer distribution may be a practical and novel strategy for effective and efficient polymorph landscape investigation, complementary to existing solvent diversifying strategies.

Research paper thumbnail of Model evaluation of particle breakage facilitated process intensification for Mixed-Suspension-Mixed-Product-Removal (MSMPR) crystallization

Chemical Engineering Science, Nov 1, 2019

Abstract This work studied a system of single stage mixed-suspension-mixed-product-removal (MSMPR... more Abstract This work studied a system of single stage mixed-suspension-mixed-product-removal (MSMPR) crystallization with particle breakage controlled by wet milling. Conventional single stage MSMPR crystallizer is limited by its degrees of freedom, which makes the process performance largely depend on steady state crystallization rate only tunable by residence time and supersaturation. Breakage brought by wet milling is demonstrated in this work as a supersaturation-independent variable to manipulate steady state conditions. The simulation results show that wet milling can act as a promising process intensification tool that increases process yield and broadens attainable region of particle size. Breakage model is adopted from dry milling and incorporated to high resolution finite volume population balance model. Four cases that cover a wide range of nucleation and growth rates have been tested, and the process yield and particle size are studied as functions of residence time and wet milling tip speeds.

Research paper thumbnail of Development of Multikilogram Continuous Flow Cyclopropanation of <i>N</i>-Benzylmaleimide through Kinetic Analysis

Organic Process Research & Development, Oct 31, 2014

A convenient and high-yielding method for the synthesis of trans-(dioxo)-azabicyclo-[3.1.0]-hexan... more A convenient and high-yielding method for the synthesis of trans-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate, a key intermediate of complex molecules, is presented using a flow cyclopropanation process. From a detailed kinetic study, it is demonstrated that the reaction concentration, addition time of reagents, and initial mixing temperature are the critical parameters to minimize formation of byproducts and to get high reaction yield. Using a modular tubular flow reactor, the trans/cis-(dioxo)azabicyclo-[3.1.0]-hexane carboxylate was obtained in 92% yield and isomerized under basic conditions to produce the transisomer in greater than 99% diastereomeric excess. Using this approach, the reaction yield was significantly increased compared to the batch process, and the robustness and reproducibility of this flow process was demonstrated for the synthesis of this key intermediate on a multikilogram scale.

Research paper thumbnail of Development of an Asymmetric Route for Large-Scale Synthesis of a Glucocorticoid Agonist

Acs Symposium Series, 2016

Research paper thumbnail of Large-Scale Enantioselective Reduction of 2,3-Disubstituted Indenopyridine Enables a Practical Manufacturing Process for an 11β-HSD-1 Inhibitor

Organic Process Research & Development, Nov 8, 2021

Research paper thumbnail of Continuous Generation of Millimeter-Sized Glycine Crystals in Non-Seeded Millifluidic Slug Flow

Crystals, Aug 9, 2019

Millimeter-sized α-glycine crystals were generated from continuous non-seeded cooling crystalliza... more Millimeter-sized α-glycine crystals were generated from continuous non-seeded cooling crystallization in slug flow. The crystallization process is composed of three steps in sequence: slug formation, crash-cooling nucleation, and growth. Stable uniform slugs of three different aspect ratios (slug length/tubing inner diameter) were formed, by adjusting the flow rates of both the solution and air streams. Besides supersaturation, the slug aspect ratio can also affect primary nucleation outcome. Stable slug flow can accommodate a relative supersaturation (C/C*) of up to 1.5 without secondary nucleation. Large glycine crystals can grow to millimeter size within 10 min, inside millimeter-sized slugs without reducing the slug quality.

Research paper thumbnail of Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)

Organic Process Research & Development, Mar 3, 2023

Research paper thumbnail of Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Green Chemistry, 2017

Supporting Information General S1 Procedures and data S2-S9 Green Aspiration Level calculations/S... more Supporting Information General S1 Procedures and data S2-S9 Green Aspiration Level calculations/Scorecard S9-S12 1 H and 13 C NMR spectra for all isolated compounds S13-S21 References S22 General. All reactions were performed under anhydrous conditions unless otherwise stated with oven-dried glassware and under an argon atmosphere. Anhydrous solvents (THF, MeOH, 1-PrOH, toluene, NMP, MeCN, and EtOAc) were purchased from Sigma-Aldrich or Fisher and were used without further purification. LDA (2 M solution in THF/EtPh/heptane) was purchased from Sigma Aldrich and used without further purification. All other starting materials and reagents were purchased from commercial sources and used as received unless otherwise noted. Melting points are uncorrected. HPLC analysis was performed on an Agilent 1200 binary pump HPLC equipped with a Zorbax Eclipse XDB-C18 4.6x50 mm column eluted at 15 °C with a mobile phase consisting of 90:10 MeCN/MeOH and water containing 0.1% H 3 PO 4 and 0.2% HClO 4. Flash chromatography was performed on a Combi-Flash system with silica column cartridges using either a dichloromethane/hexanes or ethyl acetate/hexanes solvent system. TLC was performed on EMD silica gel F254 2.5x7.5 cm plates and visualized with UV (254 nm) and/or a cerium molybdate or potassium permanganate stain. NMR spectra were recorded on Bruker 400 or 500 MHz instruments. All 1 H and 13 C NMR data were referenced to the internal deuterated solvent relative to TMS at 0 ppm. High resolution mass spectroscopy (HRMS) was performed on a TOF instrument with ESI in positive ionization mode. Flash chromatography was performed on a Combi-Flash Electronic Supplementary Material (ESI) for Green Chemistry.

Research paper thumbnail of Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)

Research paper thumbnail of Formes à l'état solide d'un inhibiteur du vih

L'invention concerne de nouvelles formes cristallines d'acide (2S)-2-tert-butoxy-2-(4-(2,... more L'invention concerne de nouvelles formes cristallines d'acide (2S)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methylquinolin-3-yl) acetique, le sel chlorhydrate de celui-ci, de nouvelles formes cristallines du sel chlorhydrate, des procedes pour la preparation de ces composes, des compositions pharmaceutiques a base de ceux-ci et leur utilisation dans le traitement d'une infection par le virus de l'immunodeficience humaine (VIH).

Research paper thumbnail of Bioavailability-Enhancing Cocrystals: Screening, In Vivo Predictive Dissolution, and Supersaturation Maintenance

Crystal Growth & Design

Research paper thumbnail of CCDC 839510: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of CCDC 839509: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of CCDC 839508: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Procede de preparation d'un polymorphe de sel de choline de derive d'acide pyrimidin-5-yl acetique

L'invention concerne un procede pour preparer un sel de choline d'acide [4,6-bis(dimethyl... more L'invention concerne un procede pour preparer un sel de choline d'acide [4,6-bis(dimethylamino)-2-(4-{ [4- (trifluoromethyl)benzoyl] amino }benzyl)pyrimidin-5-yl] acetique. Le procede de invention est utilise pour preparer le sel sous ses formes les plus pures. L'invention concerne egalement une ou plusieurs formes pures du sel de choline de l'acide [4,6-bis(dimethylamino)-2-(4-{ [4- (trifluoromethyl)benzoyl] amino }benzyl)pyrimidin-5-yl] acetique.

Research paper thumbnail of Efficient Iron-Catalyzed Kumada Cross-Coupling Reactions Utilizing Flow Technology under Low Catalyst Loadings

European Journal of Organic Chemistry, Apr 19, 2016

An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling ... more An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents in presence of low catalyst loadings (0.5 mol-%). Compared to batch mode, the continuous flow approach overcomes the exothermicity which enabled longer catalyst lifetime, facilitated scale-up and signifi-[a] Chemical Development,

Research paper thumbnail of Automated Reactions in Continuous Flow Reactors

Research paper thumbnail of ChemInform Abstract: Efficient Iron-Catalyzed Kumada Cross-Coupling Reactions Utilizing Flow Technology under Low Catalyst Loadings

ChemInform, Sep 1, 2016

Polyphenylalkane derivatives Q 0720 Efficient Iron-Catalyzed Sakurai-Michael Addition of Allyltri... more Polyphenylalkane derivatives Q 0720 Efficient Iron-Catalyzed Sakurai-Michael Addition of Allyltrimethylsilane to Chalcones.-The chemoselective reaction is catalyzed by the combination of iron(III) salts and TmsCl.

Research paper thumbnail of Bioavailability-Enhancing Cocrystals: Screening, <i>In Vivo</i> Predictive Dissolution, and Supersaturation Maintenance

Crystal Growth & Design, Aug 16, 2022

Research paper thumbnail of Development of a Practical Process for the Synthesis of PDE4 Inhibitors

Organic Process Research & Development, May 5, 2016

A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inh... more A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inhibitors represented by 1 and 2 was developed and demonstrated on a multi-kilogram scale. Key aspects of the process include the regioselective synthesis of dihydrothieno[3,2-d]pyrimidine-2,4-diol 9 and the asymmetric sulfur oxidation of intermediate 11.

Research paper thumbnail of Diverse Solvent Selection for Polymorph Landscape Investigation Based on Specific API–Solvent Interactions

Crystal Growth & Design, Feb 19, 2020

Selection of a diverse set of solvents is important for systematic investigation of polymorph lan... more Selection of a diverse set of solvents is important for systematic investigation of polymorph landscape and quick identification of the stable polymorph. The diversity of selected solvents is usually defined by solvent properties only, such as solvent functional groups, polarity, and hydrogen bonding capabilities. It is desired to customize solvent selection based on API (active pharmaceutical ingredients) molecular structures, especially API-solvent interactions related to crystallization behaviors. In this study, the crystallization related API-solvent interactions were profiled using the relative conformer distributions in solutions, which was visualized as conformer solvent maps to guide solvent selection for polymorph landscape investigation. Quantum mechanics and COSMO-SAC methods were utilized to calculate the relative distributions of representative conformers of API molecules in solutions. Interplay between relative conformer distribution and API molecular cluster in solution were studied using molecular dynamics, where virtual supersaturated solutions were simulated using large numbers of API and solvent molecules. The results suggested that relative conformer distribution could influence the structure of API molecular clusters and subsequent crystallization processes. Systematically varying the relative conformer distribution may be a practical and novel strategy for effective and efficient polymorph landscape investigation, complementary to existing solvent diversifying strategies.

Research paper thumbnail of Model evaluation of particle breakage facilitated process intensification for Mixed-Suspension-Mixed-Product-Removal (MSMPR) crystallization

Chemical Engineering Science, Nov 1, 2019

Abstract This work studied a system of single stage mixed-suspension-mixed-product-removal (MSMPR... more Abstract This work studied a system of single stage mixed-suspension-mixed-product-removal (MSMPR) crystallization with particle breakage controlled by wet milling. Conventional single stage MSMPR crystallizer is limited by its degrees of freedom, which makes the process performance largely depend on steady state crystallization rate only tunable by residence time and supersaturation. Breakage brought by wet milling is demonstrated in this work as a supersaturation-independent variable to manipulate steady state conditions. The simulation results show that wet milling can act as a promising process intensification tool that increases process yield and broadens attainable region of particle size. Breakage model is adopted from dry milling and incorporated to high resolution finite volume population balance model. Four cases that cover a wide range of nucleation and growth rates have been tested, and the process yield and particle size are studied as functions of residence time and wet milling tip speeds.

Research paper thumbnail of Development of Multikilogram Continuous Flow Cyclopropanation of <i>N</i>-Benzylmaleimide through Kinetic Analysis

Organic Process Research & Development, Oct 31, 2014

A convenient and high-yielding method for the synthesis of trans-(dioxo)-azabicyclo-[3.1.0]-hexan... more A convenient and high-yielding method for the synthesis of trans-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate, a key intermediate of complex molecules, is presented using a flow cyclopropanation process. From a detailed kinetic study, it is demonstrated that the reaction concentration, addition time of reagents, and initial mixing temperature are the critical parameters to minimize formation of byproducts and to get high reaction yield. Using a modular tubular flow reactor, the trans/cis-(dioxo)azabicyclo-[3.1.0]-hexane carboxylate was obtained in 92% yield and isomerized under basic conditions to produce the transisomer in greater than 99% diastereomeric excess. Using this approach, the reaction yield was significantly increased compared to the batch process, and the robustness and reproducibility of this flow process was demonstrated for the synthesis of this key intermediate on a multikilogram scale.

Research paper thumbnail of Development of an Asymmetric Route for Large-Scale Synthesis of a Glucocorticoid Agonist

Acs Symposium Series, 2016

Research paper thumbnail of Large-Scale Enantioselective Reduction of 2,3-Disubstituted Indenopyridine Enables a Practical Manufacturing Process for an 11β-HSD-1 Inhibitor

Organic Process Research & Development, Nov 8, 2021

Research paper thumbnail of Continuous Generation of Millimeter-Sized Glycine Crystals in Non-Seeded Millifluidic Slug Flow

Crystals, Aug 9, 2019

Millimeter-sized α-glycine crystals were generated from continuous non-seeded cooling crystalliza... more Millimeter-sized α-glycine crystals were generated from continuous non-seeded cooling crystallization in slug flow. The crystallization process is composed of three steps in sequence: slug formation, crash-cooling nucleation, and growth. Stable uniform slugs of three different aspect ratios (slug length/tubing inner diameter) were formed, by adjusting the flow rates of both the solution and air streams. Besides supersaturation, the slug aspect ratio can also affect primary nucleation outcome. Stable slug flow can accommodate a relative supersaturation (C/C*) of up to 1.5 without secondary nucleation. Large glycine crystals can grow to millimeter size within 10 min, inside millimeter-sized slugs without reducing the slug quality.

Research paper thumbnail of Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)

Organic Process Research & Development, Mar 3, 2023

Research paper thumbnail of Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Green Chemistry, 2017

Supporting Information General S1 Procedures and data S2-S9 Green Aspiration Level calculations/S... more Supporting Information General S1 Procedures and data S2-S9 Green Aspiration Level calculations/Scorecard S9-S12 1 H and 13 C NMR spectra for all isolated compounds S13-S21 References S22 General. All reactions were performed under anhydrous conditions unless otherwise stated with oven-dried glassware and under an argon atmosphere. Anhydrous solvents (THF, MeOH, 1-PrOH, toluene, NMP, MeCN, and EtOAc) were purchased from Sigma-Aldrich or Fisher and were used without further purification. LDA (2 M solution in THF/EtPh/heptane) was purchased from Sigma Aldrich and used without further purification. All other starting materials and reagents were purchased from commercial sources and used as received unless otherwise noted. Melting points are uncorrected. HPLC analysis was performed on an Agilent 1200 binary pump HPLC equipped with a Zorbax Eclipse XDB-C18 4.6x50 mm column eluted at 15 °C with a mobile phase consisting of 90:10 MeCN/MeOH and water containing 0.1% H 3 PO 4 and 0.2% HClO 4. Flash chromatography was performed on a Combi-Flash system with silica column cartridges using either a dichloromethane/hexanes or ethyl acetate/hexanes solvent system. TLC was performed on EMD silica gel F254 2.5x7.5 cm plates and visualized with UV (254 nm) and/or a cerium molybdate or potassium permanganate stain. NMR spectra were recorded on Bruker 400 or 500 MHz instruments. All 1 H and 13 C NMR data were referenced to the internal deuterated solvent relative to TMS at 0 ppm. High resolution mass spectroscopy (HRMS) was performed on a TOF instrument with ESI in positive ionization mode. Flash chromatography was performed on a Combi-Flash Electronic Supplementary Material (ESI) for Green Chemistry.

Research paper thumbnail of Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)

Research paper thumbnail of Formes à l'état solide d'un inhibiteur du vih

L'invention concerne de nouvelles formes cristallines d'acide (2S)-2-tert-butoxy-2-(4-(2,... more L'invention concerne de nouvelles formes cristallines d'acide (2S)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methylquinolin-3-yl) acetique, le sel chlorhydrate de celui-ci, de nouvelles formes cristallines du sel chlorhydrate, des procedes pour la preparation de ces composes, des compositions pharmaceutiques a base de ceux-ci et leur utilisation dans le traitement d'une infection par le virus de l'immunodeficience humaine (VIH).

Research paper thumbnail of Bioavailability-Enhancing Cocrystals: Screening, In Vivo Predictive Dissolution, and Supersaturation Maintenance

Crystal Growth & Design

Research paper thumbnail of CCDC 839510: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of CCDC 839509: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of CCDC 839508: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Procede de preparation d'un polymorphe de sel de choline de derive d'acide pyrimidin-5-yl acetique

L'invention concerne un procede pour preparer un sel de choline d'acide [4,6-bis(dimethyl... more L'invention concerne un procede pour preparer un sel de choline d'acide [4,6-bis(dimethylamino)-2-(4-{ [4- (trifluoromethyl)benzoyl] amino }benzyl)pyrimidin-5-yl] acetique. Le procede de invention est utilise pour preparer le sel sous ses formes les plus pures. L'invention concerne egalement une ou plusieurs formes pures du sel de choline de l'acide [4,6-bis(dimethylamino)-2-(4-{ [4- (trifluoromethyl)benzoyl] amino }benzyl)pyrimidin-5-yl] acetique.