Organic Process Research & Development最新文献

{"title":"Organozinc Reagents: Highly Efficient Scalable Continuous Conversion in Various Concentrations and Reaction Types","authors":"Lars Gössl, Kai Dahms, Gabriele Menges-Flanagan* and Michael Maskos, ","doi":"10.1021/acs.oprd.4c0029210.1021/acs.oprd.4c00292","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00292https://doi.org/10.1021/acs.oprd.4c00292","url":null,"abstract":"<p >Organometallic reagents play a crucial role in today’s synthetic chemistry. They are used in the production of active pharmaceutical ingredients (APIs), fragrances, and agrochemicals, among other things, as they are instrumental and invaluable to form new carbon–carbon bonds. In addition to the widely used organolithium and organomagnesium compounds, better known as Grignard reagents, organozinc compounds are predestined coupling partners in C–C bond formation. Even though organozinc compounds are among the oldest organometallic compounds, they have long been superseded by the more reactive Grignard reagents (RMgX) and lithium organyls (RLi). The low reactivity of organozinc compounds in combination with a high sensitivity to oxygen and moisture lead to difficult handling and problematic storage. Their usefulness for C–C bond formation was therefore underestimated for a long time but has experienced a renaissance in recent decades. In a previous publication, the scalable continuous synthesis of organozinc compounds in different concentrations and solvents was demonstrated. The organozinc compounds were produced in both laboratory and pilot scale with good to very good yields and the formation of highly concentrated organozinc compounds was also confirmed. To build on this work, the continuous conversion of organozinc compounds is described below. Two different reaction types were investigated: the noncatalyzed Saytzeff reaction and the palladium-catalyzed Negishi cross-coupling reaction. The former was carried out in both a two-step and a one-pot approach. The reactive allylzinc bromide was chosen as the organometallic reagent, which was reacted with various aldehydes and ketones to yield secondary or tertiary homoallyl alcohols. In the Saytzeff reaction, residence times of 2.0 min were sufficient to achieve complete conversion of the carbonyl compound and isolated yields of 66–98%. The conversion of the carbonyl compound was monitored using an online process IR spectrometer with flow cell. In the case of the Negishi coupling, a fixed-bed reactor filled with Pd catalyst was used. The syntheses investigated were focused on the reaction of benzylzinc bromide with various functionalized organic halides. The Negishi coupling provided complete to near complete conversion of the electrophilic substrate with isolated yields of 72–92% at residence times of 23–32 s. Both the Saytzeff and Negishi reactions were extended to include the conversion of highly concentrated 2.0 M organozinc compounds. The former delivered yields of 83% and 92%, the latter 72% and 79%. The Saytzeff conversion was additionally transferred to pilot scale to demonstrate the ease of scalability. The synthesis of two selected compounds was successfully transferred to pilot scale, where a liquid throughput of 13 L/h was achieved. The main objective of this work was to establish various catalyzed and noncatalyzed conversions of organozinc reagents, particularly at high organozinc re","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450550","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}

{"title":"Organozinc Reagents: Highly Efficient Scalable Continuous Conversion in Various Concentrations and Reaction Types","authors":"Lars Gössl, Kai Dahms, Gabriele Menges-Flanagan, Michael Maskos","doi":"10.1021/acs.oprd.4c00292","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00292","url":null,"abstract":"Organometallic reagents play a crucial role in today’s synthetic chemistry. They are used in the production of active pharmaceutical ingredients (APIs), fragrances, and agrochemicals, among other things, as they are instrumental and invaluable to form new carbon–carbon bonds. In addition to the widely used organolithium and organomagnesium compounds, better known as Grignard reagents, organozinc compounds are predestined coupling partners in C–C bond formation. Even though organozinc compounds are among the oldest organometallic compounds, they have long been superseded by the more reactive Grignard reagents (RMgX) and lithium organyls (RLi). The low reactivity of organozinc compounds in combination with a high sensitivity to oxygen and moisture lead to difficult handling and problematic storage. Their usefulness for C–C bond formation was therefore underestimated for a long time but has experienced a renaissance in recent decades. In a previous publication, the scalable continuous synthesis of organozinc compounds in different concentrations and solvents was demonstrated. The organozinc compounds were produced in both laboratory and pilot scale with good to very good yields and the formation of highly concentrated organozinc compounds was also confirmed. To build on this work, the continuous conversion of organozinc compounds is described below. Two different reaction types were investigated: the noncatalyzed Saytzeff reaction and the palladium-catalyzed Negishi cross-coupling reaction. The former was carried out in both a two-step and a one-pot approach. The reactive allylzinc bromide was chosen as the organometallic reagent, which was reacted with various aldehydes and ketones to yield secondary or tertiary homoallyl alcohols. In the Saytzeff reaction, residence times of 2.0 min were sufficient to achieve complete conversion of the carbonyl compound and isolated yields of 66–98%. The conversion of the carbonyl compound was monitored using an online process IR spectrometer with flow cell. In the case of the Negishi coupling, a fixed-bed reactor filled with Pd catalyst was used. The syntheses investigated were focused on the reaction of benzylzinc bromide with various functionalized organic halides. The Negishi coupling provided complete to near complete conversion of the electrophilic substrate with isolated yields of 72–92% at residence times of 23–32 s. Both the Saytzeff and Negishi reactions were extended to include the conversion of highly concentrated 2.0 M organozinc compounds. The former delivered yields of 83% and 92%, the latter 72% and 79%. The Saytzeff conversion was additionally transferred to pilot scale to demonstrate the ease of scalability. The synthesis of two selected compounds was successfully transferred to pilot scale, where a liquid throughput of 13 L/h was achieved. The main objective of this work was to establish various catalyzed and noncatalyzed conversions of organozinc reagents, particularly at high organozinc reagen","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360500","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}

{"title":"Synthesis of Enantiopure Fluoropiperidines via Biocatalytic Desymmetrization and Flow Photochemical Decarboxylative Fluorination","authors":"Caroline A. Blakemore*,&nbsp;John M. Humphrey,&nbsp;Eddie Yang,&nbsp;Jeffrey T. Kohrt,&nbsp;Peter Daniel Morse,&nbsp;Roger M. Howard,&nbsp;Hatice G. Yayla,&nbsp;Thomas Knauber,&nbsp;Longfei Xie,&nbsp;Teresa Makowski,&nbsp;Jeffrey W. Raggon,&nbsp;Rebecca B. Watson,&nbsp;Christopher W. am Ende,&nbsp;Tim Ryder,&nbsp;Ormacinda White,&nbsp;Martin R. M. Koos,&nbsp;Rajesh Kumar,&nbsp;Feng Shi,&nbsp;Jie Li,&nbsp;Huan Wang,&nbsp;Like Chen and Julai Wang,&nbsp;","doi":"10.1021/acs.oprd.4c0013910.1021/acs.oprd.4c00139","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00139https://doi.org/10.1021/acs.oprd.4c00139","url":null,"abstract":"<p >Low-molecular weight chiral amines are valuable components in medicinal chemistry as they serve as core templates, linking units, and substituent appendages. The piperidine scaffold is particularly useful among privileged small amines, with substituted variants having a great number of potential regio- and diastereoisomers, which allow for high stereochemical definition to enable a variety of productive protein interactions. Herein, we describe the successful enablement, scale-up, and delivery of &gt;400 g of a single isomer, (3<i>S</i>,5<i>S</i>)-1-((benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid (&gt;98% de and &gt;96% ee), via 450 g-scale biocatalytic desymmetrization and 335 g-scale flow photochemical decarboxylative fluorination.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449031","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}

{"title":"Synthesis of Enantiopure Fluoropiperidines via Biocatalytic Desymmetrization and Flow Photochemical Decarboxylative Fluorination","authors":"Caroline A. Blakemore, John M. Humphrey, Eddie Yang, Jeffrey T. Kohrt, Peter Daniel Morse, Roger M. Howard, Hatice G. Yayla, Thomas Knauber, Longfei Xie, Teresa Makowski, Jeffrey W. Raggon, Rebecca B. Watson, Christopher W. am Ende, Tim Ryder, Ormacinda White, Martin R. M. Koos, Rajesh Kumar, Feng Shi, Jie Li, Huan Wang, Like Chen, Julai Wang","doi":"10.1021/acs.oprd.4c00139","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00139","url":null,"abstract":"Low-molecular weight chiral amines are valuable components in medicinal chemistry as they serve as core templates, linking units, and substituent appendages. The piperidine scaffold is particularly useful among privileged small amines, with substituted variants having a great number of potential regio- and diastereoisomers, which allow for high stereochemical definition to enable a variety of productive protein interactions. Herein, we describe the successful enablement, scale-up, and delivery of &gt;400 g of a single isomer, (3<i>S</i>,5<i>S</i>)-1-((benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid (&gt;98% de and &gt;96% ee), via 450 g-scale biocatalytic desymmetrization and 335 g-scale flow photochemical decarboxylative fluorination.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330045","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}

{"title":"Economic, One-Pot Synthesis of Diethyl Furoxan Dicarboxylate","authors":"Michael Thoenen, Nicholas F. Scherschel, Davin G. Piercey","doi":"10.1021/acs.oprd.4c00191","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00191","url":null,"abstract":"Diethyl furoxan dicarboxylate (DFD) is a starting material for fields as diverse as drug discovery, energetics, and any application where a furoxan or furazan may be desired. As with many disubstituted furoxans, they are synthesized via the dimerization of the appropriate nitrile oxide. Past procedures to form DFD involve low-yield destructive nitrations, multiple steps, halogenated solvents, or heavy or precious metals. Although these methods are functional enough for lab-scale preparations of DFD, they do not hold up well for economical scale-up. Our reported procedure improves the synthesis of DFD such that it is available from economical and commercially available starting materials in a single-step, one-pot, high-yield (98.5%) synthesis of material with a trivial workup in high purity (98.2% by ¹H quantitative NMR against a 2,4,6-trimethoxy-1,3,5-triazene standard). This improved procedure requires no organic solvents or heavy metals and is the most scalable preparation for this material to date.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317778","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}

{"title":"Economic, One-Pot Synthesis of Diethyl Furoxan Dicarboxylate","authors":"Michael Thoenen,&nbsp;Nicholas F. Scherschel and Davin G. Piercey*,&nbsp;","doi":"10.1021/acs.oprd.4c0019110.1021/acs.oprd.4c00191","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00191https://doi.org/10.1021/acs.oprd.4c00191","url":null,"abstract":"<p >Diethyl furoxan dicarboxylate (DFD) is a starting material for fields as diverse as drug discovery, energetics, and any application where a furoxan or furazan may be desired. As with many disubstituted furoxans, they are synthesized via the dimerization of the appropriate nitrile oxide. Past procedures to form DFD involve low-yield destructive nitrations, multiple steps, halogenated solvents, or heavy or precious metals. Although these methods are functional enough for lab-scale preparations of DFD, they do not hold up well for economical scale-up. Our reported procedure improves the synthesis of DFD such that it is available from economical and commercially available starting materials in a single-step, one-pot, high-yield (98.5%) synthesis of material with a trivial workup in high purity (98.2% by ¹H quantitative NMR against a 2,4,6-trimethoxy-1,3,5-triazene standard). This improved procedure requires no organic solvents or heavy metals and is the most scalable preparation for this material to date.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450596","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}

{"title":"Highly Selective Electrosynthesis of 1H-1-Hydroxyquinol-4-ones–Synthetic Access to Versatile Natural Antibiotics","authors":"Tobias Prenzel, Nils Schwarz, Jasmin Hammes, Franziska Krähe, Sarah Pschierer, Johannes Winter, María de Jesús Gálvez-Vázquez, Dieter Schollmeyer, Siegfried R. Waldvogel","doi":"10.1021/acs.oprd.4c00337","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00337","url":null,"abstract":"1<i>H</i>-1-Hydroxyquinolin-4-ones represent a broad class of biologically active heterocycles having an exocyclic N,O motif. Electrosynthesis offers direct, highly selective, and sustainable access to 1-hydroxyquinol-4-ones by nitro reduction. A versatile synthetic route starting from easily accessible 2-nitrobenzoic acids was established. The broad applicability of this protocol was demonstrated on 26 examples with up to 93% yield, highlighted by the naturally occurring antibiotics Aurachin C and HQNO. The practicability and technical relevance were underlined by multigram scale electrolysis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317780","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}

{"title":"Risk of Formaldehyde Contamination in Amines from Residual Dichloromethane","authors":"Henrique A. Esteves*,&nbsp;Subha Mukherjee,&nbsp;James Chadwick,&nbsp;Jennifer Albaneze-Walker,&nbsp;Whitney Nikitczuk,&nbsp;Jonathan Marshall,&nbsp;Joanne Ly,&nbsp;Antonio Ramirez,&nbsp;Emanuele Petruzzella and Junhe Ma,&nbsp;","doi":"10.1021/acs.oprd.4c0032310.1021/acs.oprd.4c00323","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00323https://doi.org/10.1021/acs.oprd.4c00323","url":null,"abstract":"<p >Understanding the mechanism of the formation of impurities in pharmaceutical intermediates and starting materials is crucial for a successful control strategy in the manufacturing of active pharmaceutical ingredients. This paper describes how amines containing residual dichloromethane can form substantial levels of formaldehyde during short-term storage. An investigation involving 22 different amines presents evidence underpinning the role of dichloromethane (DCM) in forming formaldehyde. Additionally, control experiments combined with existing knowledge on the reactivity of DCM with amine nucleophiles provide a mechanistic discussion on the generation of formaldehyde via known adducts from the reaction between amines, dichloromethane, and water. Finally, a case study involving a key intermediate of a drug candidate under investigation at Bristol Myers Squibb demonstrates the impact of residual DCM-derived formaldehyde in amine starting material on the formation of a daughter impurity during an amidation step.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450542","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}

{"title":"Risk of Formaldehyde Contamination in Amines from Residual Dichloromethane","authors":"Henrique A. Esteves, Subha Mukherjee, James Chadwick, Jennifer Albaneze-Walker, Whitney Nikitczuk, Jonathan Marshall, Joanne Ly, Antonio Ramirez, Emanuele Petruzzella, Junhe Ma","doi":"10.1021/acs.oprd.4c00323","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00323","url":null,"abstract":"Understanding the mechanism of the formation of impurities in pharmaceutical intermediates and starting materials is crucial for a successful control strategy in the manufacturing of active pharmaceutical ingredients. This paper describes how amines containing residual dichloromethane can form substantial levels of formaldehyde during short-term storage. An investigation involving 22 different amines presents evidence underpinning the role of dichloromethane (DCM) in forming formaldehyde. Additionally, control experiments combined with existing knowledge on the reactivity of DCM with amine nucleophiles provide a mechanistic discussion on the generation of formaldehyde via known adducts from the reaction between amines, dichloromethane, and water. Finally, a case study involving a key intermediate of a drug candidate under investigation at Bristol Myers Squibb demonstrates the impact of residual DCM-derived formaldehyde in amine starting material on the formation of a daughter impurity during an amidation step.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317779","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}

{"title":"Highly Selective Electrosynthesis of 1H-1-Hydroxyquinol-4-ones–Synthetic Access to Versatile Natural Antibiotics","authors":"Tobias Prenzel,&nbsp;Nils Schwarz,&nbsp;Jasmin Hammes,&nbsp;Franziska Krähe,&nbsp;Sarah Pschierer,&nbsp;Johannes Winter,&nbsp;María de Jesús Gálvez-Vázquez,&nbsp;Dieter Schollmeyer and Siegfried R. Waldvogel*,&nbsp;","doi":"10.1021/acs.oprd.4c0033710.1021/acs.oprd.4c00337","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00337https://doi.org/10.1021/acs.oprd.4c00337","url":null,"abstract":"<p >1<i>H</i>-1-Hydroxyquinolin-4-ones represent a broad class of biologically active heterocycles having an exocyclic N,O motif. Electrosynthesis offers direct, highly selective, and sustainable access to 1-hydroxyquinol-4-ones by nitro reduction. A versatile synthetic route starting from easily accessible 2-nitrobenzoic acids was established. The broad applicability of this protocol was demonstrated on 26 examples with up to 93% yield, highlighted by the naturally occurring antibiotics Aurachin C and HQNO. The practicability and technical relevance were underlined by multigram scale electrolysis.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00337","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}