Organic Process Research & Development最新文献_第5页

Continuous Preparation of Trifluoromethyl Diazomethane in Flow Using In-Line Membrane Phase Separation─Application to the Catalytic Asymmetric Cyclopropanation of Substituted Styrenes

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-03 DOI: 10.1021/acs.oprd.4c00477

Tyler K. Allred, Olga A. Mukhina, Oleg Epstein, Jie Yan, Kevin Crossley, Matthew G. Beaver, Michael J. Frohn, James I. Murray, David Bauer

引用次数: 0

Building Efficient Diastereo- and Enantioselective Synthetic Routes to trans-Cyclopropyl Esters for Rapid Lead Scale-Up

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-03-03 DOI: 10.1021/acs.oprd.5c0000710.1021/acs.oprd.5c00007

Christophe Allais, Louise Bernier, David C. Blakemore, Jeffrey Casavant, Xiayun Cheng, Chulho Choi, Matthew Chuba, Matthew S. Corbett, Kenneth J. Dirico, William Farrell, Scott P. France, Francois Godin, Roger M. Howard, Gajendra Ingle, Daniel W. Kung, David C. Limburg, Richard P. Loach*, Vincent M. Lombardo, Hadi Rezaei, Neal W. Sach, Alexandria P. Taylor and Haresh Thakellapalli,

{"title":"Building Efficient Diastereo- and Enantioselective Synthetic Routes to trans-Cyclopropyl Esters for Rapid Lead Scale-Up","authors":"Christophe Allais, Louise Bernier, David C. Blakemore, Jeffrey Casavant, Xiayun Cheng, Chulho Choi, Matthew Chuba, Matthew S. Corbett, Kenneth J. Dirico, William Farrell, Scott P. France, Francois Godin, Roger M. Howard, Gajendra Ingle, Daniel W. Kung, David C. Limburg, Richard P. Loach*, Vincent M. Lombardo, Hadi Rezaei, Neal W. Sach, Alexandria P. Taylor and Haresh Thakellapalli, ","doi":"10.1021/acs.oprd.5c0000710.1021/acs.oprd.5c00007","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00007https://doi.org/10.1021/acs.oprd.5c00007","url":null,"abstract":"Cyclopropanes play an important role in drug discovery, and synthetic access to variedly substituted systems is an ongoing challenge for chemistry teams. A variety of scalable synthetic routes were developed and optimized for the construction of 1,2-trans-disubstituted cyclopropyl esters. The use of a stable cyclopropyl trifluoroborate provided a path for the rapid exploration of heteroaryl substituent diversity. Two asymmetric approaches were subsequently enabled as viable alternatives. Our first approach led to the development of a novel sulfoximine-driven Johnson–Corey–Chaykovsky reaction of menthyl acrylates and is the first example of this chemistry for the enantio- and diastereostereoselective construction of trans-cyclopropanes. Ultimately, a scalable process route was fashioned through the optimization of an efficient ring opening/intramolecular C–O phosphate transfer and displacement cascade that builds the trans-cyclopropyl ester from a chiral epoxide with excellent stereocontrol.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"920–931 920–931"},"PeriodicalIF":3.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Building Efficient Diastereo- and Enantioselective Synthetic Routes to trans-Cyclopropyl Esters for Rapid Lead Scale-Up

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-03 DOI: 10.1021/acs.oprd.5c00007

Christophe Allais, Louise Bernier, David C. Blakemore, Jeffrey Casavant, Xiayun Cheng, Chulho Choi, Matthew Chuba, Matthew S. Corbett, Kenneth J. Dirico, William Farrell, Scott P. France, Francois Godin, Roger M. Howard, Gajendra Ingle, Daniel W. Kung, David C. Limburg, Richard P. Loach, Vincent M. Lombardo, Hadi Rezaei, Neal W. Sach, Alexandria P. Taylor, Haresh Thakellapalli

{"title":"Building Efficient Diastereo- and Enantioselective Synthetic Routes to trans-Cyclopropyl Esters for Rapid Lead Scale-Up","authors":"Christophe Allais, Louise Bernier, David C. Blakemore, Jeffrey Casavant, Xiayun Cheng, Chulho Choi, Matthew Chuba, Matthew S. Corbett, Kenneth J. Dirico, William Farrell, Scott P. France, Francois Godin, Roger M. Howard, Gajendra Ingle, Daniel W. Kung, David C. Limburg, Richard P. Loach, Vincent M. Lombardo, Hadi Rezaei, Neal W. Sach, Alexandria P. Taylor, Haresh Thakellapalli","doi":"10.1021/acs.oprd.5c00007","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00007","url":null,"abstract":"Cyclopropanes play an important role in drug discovery, and synthetic access to variedly substituted systems is an ongoing challenge for chemistry teams. A variety of scalable synthetic routes were developed and optimized for the construction of 1,2-trans-disubstituted cyclopropyl esters. The use of a stable cyclopropyl trifluoroborate provided a path for the rapid exploration of heteroaryl substituent diversity. Two asymmetric approaches were subsequently enabled as viable alternatives. Our first approach led to the development of a novel sulfoximine-driven Johnson–Corey–Chaykovsky reaction of menthyl acrylates and is the first example of this chemistry for the enantio- and diastereostereoselective construction of trans-cyclopropanes. Ultimately, a scalable process route was fashioned through the optimization of an efficient ring opening/intramolecular C–O phosphate transfer and displacement cascade that builds the trans-cyclopropyl ester from a chiral epoxide with excellent stereocontrol.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"211 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Use of Ni(cod)(dq) (COD: 1,5-Cyclooctadiene; DQ: Duroquinone) for the Dehalogenative Coupling Polycondensation to π-Conjugated Polyarylenes

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-02 DOI: 10.1021/acs.oprd.5c00012

Naoki Noda, Maho Umeda, Kentaro Okano, Kuei-Cheng Chen, Masaki Horie, Atsunori Mori

{"title":"The Use of Ni(cod)(dq) (COD: 1,5-Cyclooctadiene; DQ: Duroquinone) for the Dehalogenative Coupling Polycondensation to π-Conjugated Polyarylenes","authors":"Naoki Noda, Maho Umeda, Kentaro Okano, Kuei-Cheng Chen, Masaki Horie, Atsunori Mori","doi":"10.1021/acs.oprd.5c00012","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00012","url":null,"abstract":"Ni(cod)(dq) (COD: 1,5-cyclooctadiene; DQ: duroquinone) with an appropriate bipyridine ligand is available for the dehalogenative polycondensation of dihaloarenes to afford π-conjugated polymers. The reaction of 2,7-dibromo-9,9-di(n-hexylfluorene) with a nickel complex composed of Ni(cod)(dq) and 4,4′-di-tert-butyl-2,2′-bipyridine in DMF/toluene (1:4) proceeded at 120 °C for 72 h. Polyfluorene was obtained in 81% yield with Mn = 13,000 (Mw/Mn = 2.0). Ni(cod)(dq) was found to be stored under an ambient atmosphere at room temperature, the use of which after several months vs a freshly opened nickel complex resulted to afford the corresponding polymer in a comparable yield and molecular weight. Other dihaloarenes such as fluorene with different alkyl chain structures, 1,4- and 1,3-dihalobenzenes, 5,5′-dibromo-2,2′-bithiophene, and 2,6-dibromo-cyclopentadithiophene, also underwent dehalogenative polymerization to afford the corresponding conjugated polymers in excellent yields with an appropriate degree of polymerization.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"56 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Use of Ni(cod)(dq) (COD: 1,5-Cyclooctadiene; DQ: Duroquinone) for the Dehalogenative Coupling Polycondensation to π-Conjugated Polyarylenes

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-03-02 DOI: 10.1021/acs.oprd.5c0001210.1021/acs.oprd.5c00012

Naoki Noda, Maho Umeda, Kentaro Okano, Kuei-Cheng Chen, Masaki Horie and Atsunori Mori*,

{"title":"The Use of Ni(cod)(dq) (COD: 1,5-Cyclooctadiene; DQ: Duroquinone) for the Dehalogenative Coupling Polycondensation to π-Conjugated Polyarylenes","authors":"Naoki Noda, Maho Umeda, Kentaro Okano, Kuei-Cheng Chen, Masaki Horie and Atsunori Mori*, ","doi":"10.1021/acs.oprd.5c0001210.1021/acs.oprd.5c00012","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00012https://doi.org/10.1021/acs.oprd.5c00012","url":null,"abstract":"Ni(cod)(dq) (COD: 1,5-cyclooctadiene; DQ: duroquinone) with an appropriate bipyridine ligand is available for the dehalogenative polycondensation of dihaloarenes to afford π-conjugated polymers. The reaction of 2,7-dibromo-9,9-di(n-hexylfluorene) with a nickel complex composed of Ni(cod)(dq) and 4,4′-di-tert-butyl-2,2′-bipyridine in DMF/toluene (1:4) proceeded at 120 °C for 72 h. Polyfluorene was obtained in 81% yield with Mn = 13,000 (Mw/Mn = 2.0). Ni(cod)(dq) was found to be stored under an ambient atmosphere at room temperature, the use of which after several months vs a freshly opened nickel complex resulted to afford the corresponding polymer in a comparable yield and molecular weight. Other dihaloarenes such as fluorene with different alkyl chain structures, 1,4- and 1,3-dihalobenzenes, 5,5′-dibromo-2,2′-bithiophene, and 2,6-dibromo-cyclopentadithiophene, also underwent dehalogenative polymerization to afford the corresponding conjugated polymers in excellent yields with an appropriate degree of polymerization.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"932–937 932–937"},"PeriodicalIF":3.1,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Fine Chemical Industry, 2000–2024

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-28 DOI: 10.1021/acs.oprd.5c00010

Rosaria Ciriminna, Cristina Della Pina, Rafael Luque, Mario Pagliaro

引用次数: 0

Improving Solid-State Properties of the Side-Chain Peptide Building Blocks for the Synthesis of GLP-1 Analogs through Their Complexation with Metal Cations

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-28 DOI: 10.1021/acs.oprd.4c00515

Andrea Orlandin, Ivan Guryanov, Chiara Giraldo, Barbara Biondi, Angelo Santoro, Marco Macis, Walter Cabri, Anna Maria D’Ursi, Antonella Glisenti, Fernando Formaggio, Antonio Ricci

{"title":"Improving Solid-State Properties of the Side-Chain Peptide Building Blocks for the Synthesis of GLP-1 Analogs through Their Complexation with Metal Cations","authors":"Andrea Orlandin, Ivan Guryanov, Chiara Giraldo, Barbara Biondi, Angelo Santoro, Marco Macis, Walter Cabri, Anna Maria D’Ursi, Antonella Glisenti, Fernando Formaggio, Antonio Ricci","doi":"10.1021/acs.oprd.4c00515","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00515","url":null,"abstract":"Glucagon-like peptide-1 analogs are receiving exponential attention for the treatment of type II diabetes and controlling weight due to their unique structure with non-natural lipidated side chains. However, the industrial-scale manufacturing of such peptides poses noticeable challenges due to the gel-like appearance of the peptide intermediates used to form the branched structure. Here, we found an efficient approach for the complexation of these protected peptide building blocks with magnesium chloride, which allows for obtaining free-flowing stable solids suitable for the more process-friendly synthesis of the peptides. A screening of the solvents and magnesium chloride content allowed us to determine the optimal parameters for the preparation of the complexes. NMR spectral analysis showed the involvement of amide groups in the interaction with the magnesium salt. Lastly, the efficiency of the coupling of the Mg-complexed lipidated side-chain building blocks was confirmed for the synthesis of tirzepatide and semaglutide fragments, showing a comparable performance with respect to the noncomplexed derivatives.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"2 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Improving Solid-State Properties of the Side-Chain Peptide Building Blocks for the Synthesis of GLP-1 Analogs through Their Complexation with Metal Cations

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-02-28 DOI: 10.1021/acs.oprd.4c0051510.1021/acs.oprd.4c00515

Andrea Orlandin, Ivan Guryanov*, Chiara Giraldo, Barbara Biondi, Angelo Santoro, Marco Macis, Walter Cabri, Anna Maria D’Ursi, Antonella Glisenti, Fernando Formaggio and Antonio Ricci*,

{"title":"Improving Solid-State Properties of the Side-Chain Peptide Building Blocks for the Synthesis of GLP-1 Analogs through Their Complexation with Metal Cations","authors":"Andrea Orlandin, Ivan Guryanov*, Chiara Giraldo, Barbara Biondi, Angelo Santoro, Marco Macis, Walter Cabri, Anna Maria D’Ursi, Antonella Glisenti, Fernando Formaggio and Antonio Ricci*, ","doi":"10.1021/acs.oprd.4c0051510.1021/acs.oprd.4c00515","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00515https://doi.org/10.1021/acs.oprd.4c00515","url":null,"abstract":"Glucagon-like peptide-1 analogs are receiving exponential attention for the treatment of type II diabetes and controlling weight due to their unique structure with non-natural lipidated side chains. However, the industrial-scale manufacturing of such peptides poses noticeable challenges due to the gel-like appearance of the peptide intermediates used to form the branched structure. Here, we found an efficient approach for the complexation of these protected peptide building blocks with magnesium chloride, which allows for obtaining free-flowing stable solids suitable for the more process-friendly synthesis of the peptides. A screening of the solvents and magnesium chloride content allowed us to determine the optimal parameters for the preparation of the complexes. NMR spectral analysis showed the involvement of amide groups in the interaction with the magnesium salt. Lastly, the efficiency of the coupling of the Mg-complexed lipidated side-chain building blocks was confirmed for the synthesis of tirzepatide and semaglutide fragments, showing a comparable performance with respect to the noncomplexed derivatives.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"785–793 785–793"},"PeriodicalIF":3.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safe and Efficient Continuous Flow Synthesis of (3S,4S)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone via Vertical Dynamic Reactor

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-02-27 DOI: 10.1021/acs.oprd.4c0050710.1021/acs.oprd.4c00507

Kai Fu, Guangbing Zheng, Xibo Guan, Haibo Mu, Xianqiang Meng, Shouxiang Jiang, Bin Wang, Guangkun Dong and Gengxiu Zheng*,

{"title":"Safe and Efficient Continuous Flow Synthesis of (3S,4S)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone via Vertical Dynamic Reactor","authors":"Kai Fu, Guangbing Zheng, Xibo Guan, Haibo Mu, Xianqiang Meng, Shouxiang Jiang, Bin Wang, Guangkun Dong and Gengxiu Zheng*, ","doi":"10.1021/acs.oprd.4c0050710.1021/acs.oprd.4c00507","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00507https://doi.org/10.1021/acs.oprd.4c00507","url":null,"abstract":"The H2O2-mediated cleavage of chiral auxiliary as a mild and selective method is commonly used in the pharmaceutical industry but they can also introduce unexpected safety hazards due to the O2 release. Here, a novel safe and efficient continuous flow synthesis process for (3S,4S)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone (4-BMA), a key intermediate of meropenem was reported. The vertical dynamic reactor (VDR) effectively addresses the safety risk by preventing electrostatic accumulation and eliminating gas-phase space within the reactor. Compared to the current batch process, the continuous flow synthesis method reported in this paper not only significantly improved the safety of the process but also greatly shortened the reaction time (from 600 to 20 min) and increased the yield (from 85 to 91%) due to its high mass and heat transfer efficiency. These results indicated that the VDR provides great potential for the industrial scale-up of 4-BMA.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"778–784 778–784"},"PeriodicalIF":3.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Scalable Flow Electrolysis of Heterogeneous Mixtures Using a Rotating Cylinder Electrode Reactor: Access to a Chiral Iminophosphorane

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-27 DOI: 10.1021/acs.oprd.4c00532

Felix Xu, Longrui Chen, Dan Lehnherr, François Lévesque

{"title":"A Scalable Flow Electrolysis of Heterogeneous Mixtures Using a Rotating Cylinder Electrode Reactor: Access to a Chiral Iminophosphorane","authors":"Felix Xu, Longrui Chen, Dan Lehnherr, François Lévesque","doi":"10.1021/acs.oprd.4c00532","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00532","url":null,"abstract":"We report the application of rotating cylinder electrode (RCE) reactors for the electrolysis of heterogeneous reactions in batch and in recirculating flow. A scalable method for the synthesis of an N-cyano iminophosphorane ligand in an RCE reactor is also reported. In the development of this process, a graphite felt attached to the inner impervious graphite was used as a rotating anode, and the outer stainless steel wall of the reactor was used as the cathode. The reaction was first evaluated in batch using a small RCE reactor to optimize the spinning rate, supporting electrolyte, and current density. The optimal batch condition was then scaled up in a medium-sized RCE reactor with modifications to adapt it to a flow process. The electrosynthesis was demonstrated up to a 100 g scale, and the impact of the reaction temperature was investigated. Finally, an operationally simple direct crystallization using water as the antisolvent provided a chiral N-cyano iminophosphorane ligand in 74% isolated yield on a 100 g scale from commercially available (S)-BINAP and bis(trimethylsilyl)carbodiimide.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0