title string | abstract string | doi string | has_route int64 |
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Development of a Catalytic Cuprate 1,6-Conjugate Dienone Addition Process for the Manufacture of Fulvestrant EAS, a Key Intermediate in the Synthesis of Fulvestrant | The paper describes the development of a process to a key steroidal intermediate in fulvestrant, the active pharmaceutical ingredient of the anticancer agent Faslodex. Synthesis of the intermediate, known within AstraZeneca as fulvestrant EAS, involves the copper-catalysed 1,6-conjugate addition of a Grignard reagent t... | 10.1021/op1001319 | 1 |
A Practical Synthesis of the PDE4 Inhibitor, KW-4490 | A practical and scalable synthesis of a PDE4 inhibitor KW-4490 ( 1 ) was developed. This improved synthesis features the construction of the 1-arylcyclohexene ( 9 ) by the Diels−Alder reaction followed by a newly established Brønsted acid-promoted hydrocyanation. Subsequent crystallization-induced dynamic resolution en... | 10.1021/op1001287 | 1 |
A Scalable Synthesis of a 1,7-Naphthyridine Derivative, a PDE-4 Inhibitor | A six-step synthesis of a 4-[8-(3-fluorophenyl)[1,7]naphthyridin-6-yl]- trans -cyclohexanecarboxylic acid with an overall yield of 27% starting from 2-cyano-3-methylpyridine, cyclohexane-1,4-dicarboxylic acid dimethyl ester, and 3-fluorophenylboronic acid is described. The trans stereochemistry in the cyclohexane moiet... | 10.1021/op100124x | 1 |
An Automated Microfluidic System for Online Optimization in Chemical Synthesis | An automated, continuous flow system for the online, multivariable optimization of a chemical reaction is presented. Time and material required for an optimization trial are minimized by performing reactions in an integrated silicon microreactor and incorporating an HPLC for inline monitoring of the reaction performanc... | 10.1021/op100123e | 0 |
Development of a Dynamic Kinetic Resolution for the Isolation of an Intermediate in the Synthesis of Casopitant Mesylate: Application of QbD Principles in the Definition of the Parameter Ranges, Issues in the Scale-Up and Mitigation Strategies | Process development towards the improvement of the manufacturing process of casopitant mesylate (a drug developed by GlaxoSmithKline with activity on the central nervous system) identified a dynamic kinetic resolution opportunity for the improvement of the yield. In this paper, the application of quality by design prin... | 10.1021/op100121s | 1 |
Process Research and Development of a MTP Inhibitor: Another Case of Disappearing Polymorphs upon Scale-up | LAB687 is an inhibitor of microsomal triglyceride transfer protein (MTP) designed to lower triglycerides and LDL cholesterol. The discovery of its polymorphic forms closely intertwines with the synthesis development of the molecule. At the early development stage, LAB687 was known to crystallize in two modifications, F... | 10.1021/op100115u | 0 |
Overall Synthesis of GSK356278: Quick Delivery of a PDE4 Inhibitor Using a Fit-for-Purpose Approach | The family of phosphodiesterase (PDE) enzymes hydrolyse cyclic nucleotides, cAMP and cGMP, leading to their inactivation as intracellular second messengers. Inhibition of these enzymes leads to an elevation of levels of cyclic nucleotides in the cell and prolongs their action on downstream signaling pathways. PDE4, of ... | 10.1021/op1001148 | 1 |
Development of a Pilot-Plant-Scale Synthesis of an Alkylated Dihydrobenzothiadiazole <i>S</i>,<i>S</i>-Dioxide: Incorporation of a Late-Stage Mitsunobu Reaction | The process used to prepare a functionalized dihydrobenzothiadiazole S, S -dioxide on a pilot plant scale is described. Key changes to the original synthesis included: modifying S N Ar reaction conditions between a substituted aniline and 2-fluoronitrobenzene from n -BuLi/−78 °C to KO t Am/0 to 15 °C; replacement of a ... | 10.1021/op100113j | 1 |
Process Development for a Large Scale Stereoselective Synthesis of (<i>Z</i>)-(1-Bromobut-1-ene-1,2-diyl)dibenzene, a Key Intermediate of a Selective Estrogen Receptor Modulator | Two efficient large scale syntheses of ( Z )-(1-bromobut-1-ene-1,2-diyl)dibenzene are described. The first is a three-step synthetic sequence from trimethyl(phenylethynyl)silane in 63% overall yield. The key transformations involved the stereospecific carbometalation reaction of trimethyl(phenylethynyl)silane followed ... | 10.1021/op100112r | 1 |
Scaling Up Attrition-Enhanced Deracemization by Use of an Industrial Bead Mill in a Route to Clopidogrel (Plavix) | The recently discovered technique of deracemization by means of grinding a racemic conglomerate in contact with a solution wherein racemization occurs has been scaled up using an industrial bead mill to demonstrate the practical applicability. The time needed to reach the enantiopure end state is drastically reduced as... | 10.1021/op1001116 | 0 |
A New and Efficient Synthesis of 6-[(5<i>S</i>,9<i>R</i>)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic Acid, a Potent LFA-1/ICAM Inhibitor | An efficient synthesis of 6-[(5 S,9 R )-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic acid 1 is described. This new process involves an in situ protection of 6-chloronicotinic acid as trimethylsilyl ester followed by coupling with spirocyclic hydantoin core 2 to gi... | 10.1021/op100104z | 1 |
Development of an Efficient Large-Scale Synthesis for a 4<i>H</i>-imidazo[5,1-<i>c</i>][1,4]benzoxazine-3-carboxamide Derivative for Depression and Anxiety | The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A low... | 10.1021/op100103v | 1 |
A Facile Microwave-Mediated Drying Process of Thermally Unstable / Labile Products | The drying behavior of ( S )- N -acetylindoline-2-carboxylic acid, precipitated ( 1a, 17 wt %) and nonprecipitated ( 1b, 5 wt %), and N -acetyl-( S )-phenylalanine (( S )-2-acetamido-3-phenylpropanoic acid, 2 ), both pharmaceutical intermediates, and of cocarboxylase hydrochloride (thiamine pyrophosphate, 3 ), a coenzy... | 10.1021/op100102m | 0 |
Process Development and Large-Scale Synthesis of a c-Met Kinase Inhibitor | A highly convergent synthesis of c-Met kinase inhibitor 1 has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4 . The chirality in sulfamide side chain 3 was installed using the cheap and readily available starting m... | 10.1021/op100101q | 1 |
Improved Process for the Preparation of 1-Benzhydrylazetidin-3-ol: Development of an Efficient Synthesis and Identification of Process-related Impurities and/or Intermediates | An improved, one-pot, and multikilogram-scale synthesis of 1-benzhydrylazetidin-3-ol, the pharmaceutically important moiety, has been developed. The improved process for the preparation of 1-benzhydrylazetidin-3-ol was able to minimize a content of impurities and allows the effective production of 1-benzhydrylazetidin-... | 10.1021/op100100y | 0 |
A Novel Scalable Synthesis of Pramipexole | Pramipexole is a dopamine D 2 subfamily receptor agonist that is used for the treatment of Parkinson’s disease. We report here on the successful application of the Fukuyama alkylation protocol to the development of a novel and scalable process for synthesis of pramipexole and its pharmaceutically acceptable salts. The ... | 10.1021/op1000989 | 1 |
The Synthesis of GV143253A: A Case Study for the Use of Analytical and Statistical Tools to Elucidate the Reaction Mechanism and to Optimize the Process | GV143253A 1 is a broad-spectrum injectable β-lactam belonging to the class of trinem antibiotics. This article describes the work which enabled a detailed process understanding via several analytical techniques and the subsequent optimization of a key intermediate. By means of a combined application of 31 P NMR spectro... | 10.1021/op100097c | 1 |
Novel Preparation of H<sub>1</sub> Receptor Antagonist Fexofenadine | A novel synthetic route for the preparation of H 1 receptor antagonist fexofenadine is described. The synthetic route started from the para-substituted aromatic derivative of methyl 4-(cyanomethyl)benzoate, 2, and gave fexofenadine in 26.0% overall yield via six steps. The whole process featured a method wherein fexofe... | 10.1021/op100090j | 1 |
Scaleup of Lipase-Catalyzed Polyester Synthesis | One of the critical steps for the commercialization of new enzyme-based products is the successful scaleup of the catalyzed reaction. In the study presented here, we achieved a scaleup for the enzymatic production of glycerol adipate on a 500 g scale in a heated, solvent-free system. The influence of various reaction c... | 10.1021/op1000868 | 0 |
Process for the Preparation of an Amorphous, Peptide-like Diabetes Drug: Approach to a Chromatography-Free Process | A manufacturing process suitable for large-scale production of the peptide-like amorphous compound N -((2 R )-1-{(3 R )-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2 H )-yl}-3-(1 H -indol-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1 H -indol-2-yl)carbonyl]piperidine-4-carboxamide (1) as a drug for treating diabe... | 10.1021/op100084r | 1 |
Development of a Control Strategy for a Defluorinated Analogue in the Manufacturing Process of Casopitant Mesylate | Casopitant mesylate was identified as part of the search for drugs with activity on the Central Nervous System (CNS) by GlaxoSmithKline. During late-phase development studies to develop the manufacturing process, a new impurity was found. This synthetic impurity, a defluorinated analogue of the drug substance, is discu... | 10.1021/op1000836 | 0 |
A Commercial Continuous Flow Microwave Reactor Evaluated for Scale-Up | Six pharmaceutically relevant reactions covering a range of physical parameters have been investigated in a commercially available microwave flow reactor. The reaction conditions were scaled-up from tube or large batch scale microwave conditions, largely without change. Energy consumption measurements were also taken. ... | 10.1021/op100082w | 1 |
Davis Oxaziridine-Mediated Asymmetric Synthesis of Proton Pump Inhibitors Using DBU Salt of Prochiral Sulfide | A simple and clean asymmetric synthesis of proton pump inhibitors using inexpensive 10-camphorsulfonyl oxaziridine is described. Here, we report the activation of prochiral sulfide by making the DBU salt that is capable of enhancing the reactivity and enantioselectivity. | 10.1021/op100075v | 0 |
Selection and Development of the Manufacturing Route for EP<sub>1</sub> Antagonist GSK269984B | A potential manufacturing route for the EP 1 antagonist GSK269984B was developed. Four synthetic approaches were examined, and a successful realisation of each is presented. The rationale supporting selection of the preferred route is discussed. This route utilised a phenolic aldol reaction as the key step and relied o... | 10.1021/op100072y | 1 |
A Tool for the Semiquantitative Assessment of Potentially Genotoxic Impurity (PGI) Carryover into API Using Physicochemical Parameters and Process Conditions | ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTA Tool for the Semiquantitative Assessment of Potentially Genotoxic Impurity (PGI) Carryover into API Using Physicochemical Parameters and Process ConditionsAndrew Teasdale*, Simon Fenner, Andrew Ray, Agnes Ford, and Andrew PhillipsView Author Information AstraZe... | 10.1021/op100071n | 0 |
Enantioselective Synthesis of (1<i>R</i>,2<i>S</i>)-1-Amino-2-vinylcyclopropanecarboxylic Acid Ethyl Ester (Vinyl-ACCA-OEt) by Asymmetric Phase-Transfer Catalyzed Cyclopropanation of (<i>E</i>)-<i>N</i>-Phenylmethyleneglycine Ethyl Ester | A concise asymmetric synthesis of (1 R,2 S )-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester, a key intermediate in the preparation of many hepatitis C virus inhibitors, is described. Stereoselective cyclopropanation of ( E )- N -phenylmethyleneglycine ethyl ester was effected by treatment with trans -1,4-dibrom... | 10.1021/op100070d | 1 |
Synthesis of Hexanitrostilbene (HNS) using a Kenics Static Mixer | Previous work on a Shipp−Kaplan type synthesis of hexanitrostilbene (HNS) using a Kenics static mixer (ref 1, from Chemineer Ltd., Cranmer Road, West Meadows, Derby DE21 6XT, UK; www.chemineer.com) has been extended by using a larger mixer (9.5 mm vs 4.75 mm OD), enabling the scale to be increased from 2.5 g to 25 g of... | 10.1021/op1000644 | 0 |
Application of the QbD Principles in the Development of the Casopitant Mesylate Manufacturing Process. Process Research Studies for the Definition of the Control Strategy of some Drug Substance-CQAs for Stages 2a, 2b, and 2c | Casopitant was identified as a potent NK 1 antagonist by GlaxoSmithKline (GSK). It was selected as part of a wide drug discovery programme within GSK for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders, and others. The mesylate salt of ca... | 10.1021/op1000622 | 1 |
A Practical Preparation of Ethyl<i>N</i>-Acyl-2-(dimethoxyphosphoryl)glycinate | A practical, cost-effective preparation of ethyl N -acyl-2-(dimethoxyphosphoryl)glycinate has been developed. The two-step process achieved an 80% overall isolated yield. | 10.1021/op1000594 | 1 |
Efficient Synthesis of Imidazoles from Aldehydes and 1,2-Diketones under Superheating Conditions by Using a Continuous Flow Microreactor System under Pressure | A simple and efficient method for the synthesis of 2,4,5-trisubstituted imidazoles has been developed by using a continuous flow microreactor system under pressure; aryl-, alkyl-, and heteroaryl-substituted imidazoles were obtained in high yields within 2 min under superheating conditions. | 10.1021/op100058h | 0 |
Efficient Synthesis of 1,3-Dialkylimidazolium-Based Ionic Liquids: The Modified Continuous Radziszewski Reaction in a Microreactor Setup | By making use of a modified Radziszewski reaction, it is demonstrated that water-soluble 1,3-dialkylimidazolium-based ionic liquids can be produced in good yields (70−90%) and purities (>95%) starting from readily available, cost-effective monoalkylamines, glyoxal, formaldehyde, and mineral or organic acids. The homosu... | 10.1021/op100055f | 1 |
Process Development of Selectively Benzoylated and Fluorinated Glycosyl Donors | Route selection, process development and large-scale preparation of selectively benzoylated and fluorinated d -glucopyranoses, required as glycosyl donors for the synthesis of the SGLT inhibitor SAR7226, are discussed. | 10.1021/op100053k | 1 |
Manufacturing Synthesis of 5-Substituted Phthalides | A manufacturing synthesis of 5-chlorophthalide has been elaborated. The key step of the procedure is ortho-lithiation of 4-chloro -N,N -diisopropylbenzamide, followed by formylation with dimethyl formamide. Reduction of the formyl moiety and subsequent ring closure, which can be carried out also in one pot, led to 5-ch... | 10.1021/op100049t | 1 |
Pilot-Plant Preparation of 3,4-Dihydropyridin-2-one Derivatives, the Core Structures of P2X<sub>7</sub>Receptor Antagonists | The pilot-plant syntheses of 3 and 4, the core structures of a series of P2X 7 antagonists are described. The sole stereogenic center in the dihydropyridinone ring was generated by catalytic desymmetrization. Selective formylation, followed by a tandem imination/lactamization sequence, produced the 3,4-dihydropyridin-2... | 10.1021/op1000447 | 1 |
Concise Synthesis of<i>C</i><sub>2</sub>-Symmetrical 2,6-Disubstituted Morpholines by<i>N → O</i>Boc Migration under SL-PTC Conditions | A novel, straightforward synthesis of enantiomerically pure 2,6-disubstituted morpholines has been developed. The ring-opening of epoxides with TsNHBoc under solid−liquid phase transfer catalysis conditions occurred with N → O migration of the Boc group, affording an intermediate carbonate that has been easily transfor... | 10.1021/op1000435 | 0 |
Preparation of Polymers under Phase-Transfer Catalytic Conditions | The application of phase-transfer catalytic (PTC) conditions leading to substantial improvements in numerous polymerization reactions is described. Generally, better yields as well as faster and cleaner reactions are achieved compared to reactions under conventional conditions. Owing to their ionic mechanisms, polycond... | 10.1021/op100040x | 0 |
Total Synthesis of Hematoporphyrin and Protoporphyrin: A Conceptually New Approach | The total synthesis of protoporphyrin IX and its disodium salt using a new alternative method to the classical MacDonald condensation is reported. The key step is the reaction of the new unsymmetrical diiodo dipyrrylmethane 1 with the known dipyrrylmethane 2 . Coupling of the two fragments leads directly to porphyrin 3... | 10.1021/op100036c | 1 |
Substituents Effect on the Erlenmeyer−Plochl Reaction: Understanding an Observed Process Reaction Time | A systematic study on hippuric acid substituents was performed in order to better understand the influence of stereoelectronic factors on the Erlenmeyer reaction rate. In addition, two reaction systems were evaluated: Hünig’s base solvent free conditions and catalytic sodium acetate in 2-methyl-THF. The effect on react... | 10.1021/op100032s | 0 |
One-Pot Synthesis of Optically Active β-Amino-α-methylene Carbonyl Derivatives From α-Amidosulfones Using Quinine-Based Phase-Transfer Catalysts | Optically active β-amino-α-methylene carbonyl derivatives (aza-Morita−Baylis−Hillman adducts) were prepared using a one-pot protocol involving an enantioselective Mannich reaction catalyzed by various quinine-based catalysts, followed by a Horner olefination. | 10.1021/op1000308 | 0 |
Expedited Development through Parallel Reaction Screening: Application to PTC-Mediated Knoevenagel Condensation | Parallel microreactor screening enabled rapid identification of effective conditions for PTC-mediated Knoevenagel condensation between aldehyde ( 1 ) and thiazalone ( 2 ), affording a dramatic reduction in cycle time when compared to traditional conditions. Interesting facets of the reaction mechanism were revealed fro... | 10.1021/op100026u | 0 |
Formation of (<i>S</i>)-5-Cyclohexyl-5-phenyl-1,3-dioxolane-2,4-dione: A Key Intermediate in the Synthesis of (<i>S</i>)-Oxybutynin Hydrochloride | The synthesis of the drug candidate ( S )-oxybutynin hydrochloride 1 is described. The procedure involves initial activation of ( S )-cyclohexylmandelic acid 2, using isobutylchloroformate, followed by reaction of the resulting intermediate with 4-(diethylamino)but-2-yn-1-ol, 3 . In this reaction, ( S )-5-cyclohexyl-5-... | 10.1021/op100021w | 0 |
Practical Asymmetric Synthesis of RO5114436, a CCR5 Receptor Antagonist | A practical asymmetric synthesis of a 3,7-diazabicyclo[3.3.0]octane derivative ( 1 ), a representative of a new class of potent CCR5 receptor antagonists, is described. The benzylamine stereogenic center of 1 was introduced by a ruthenium-catalyzed asymmetric reductive amination using ( R )-MeOBIPHEP as ligand. Aldehyd... | 10.1021/op100020z | 1 |
An Improved Process for the Synthesis of 5-Bromo-3-(1-methylpiperidin-4-yl)-1<i>H</i>-indole: A Key Intermediate in the Synthesis of Naratriptan Hydrochloride | An improved process has been developed for the synthesis of 5-bromo-3-(1-methylpiperidin-4-yl)-1 H -indole, a key intermediate of naratriptan hydrochloride, which is used as a drug for migraine. A novel one-pot synthetic procedure using triethyl silane was developed for scale-up. | 10.1021/op100018r | 1 |
A Novel Hybrid Chromatography−Crystallization Process for the Isolation and Purification of a Natural Pharmaceutical Ingredient from a Medicinal Herb | In this work, a hybrid chromatography−crystallization separation process is suggested and is used to isolate and purify the antimalarial drug artemisinin from the Chinese medicinal herb Artemisia annua . Extraction of the aerial parts of A. annua by an organic solvent yielded a complex mixture of natural products. A hy... | 10.1021/op1000176 | 0 |
Safe and Scaleable Oxidation of Benzaldoximes to Benzohydroximinoyl Chlorides<sup>†</sup> | Benzohydroximinoyl chlorides are useful precursors to nitrile oxides used in the preparation of various heterocycles via 1,3-dipolar cycloadditions. These intermediates are typically accessed by oxidation of aldoximes using N -chlorosuccinimide. This simple and efficient reaction is highly exothermic and a significant ... | 10.1021/op100013m | 0 |
Development of a Scaleable Process for the Synthesis of a Next-Generation Statin | This manuscript details the process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,... | 10.1021/op100010n | 1 |
Development of a Kilogram-Scale Asymmetric Synthesis of a Potent DP Receptor Antagonist | An efficient asymmetric synthesis of a unique sulfenylated prostaglandin DP receptor antagonist candidate is described. The synthesis is characterized by a novel intramolecular Friedel−Crafts cyclization of an imino-pyrrole to prepare the azaindole core. Other key steps include a highly selective Horner−Wadsworth−Emmon... | 10.1021/op100008m | 1 |
Selective Crystallization of an Allylic 7α-Bromide: A Facile Synthesis of (1α,3β)-3-Hydroxycholeste-5,7-diene-1,25-diol Diacetate | ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionSelective Crystallization of an Allylic 7α-Bromide: A Facile Synthesis of (1α,3β)-3-Hydroxycholeste-5,7-diene-1,25-diol DiacetateSusan D. Van Arnum, Barry K. Carpenter, Harold Moffet, David R. Parrish, Archibald MacIntyre... | 10.1021/op068015q | 0 |
Cyclopentyl Methyl Ether as a New and Alternative Process Solvent | Cyclopentyl methyl ether (CPME) has become available in commercial quantities since November 2005 from Zeon Corporation with approval by the Toxic Substances Control Act (TSCA) and the European List of Notified Chemical Substances (ELINCS). A high boiling point (106 °C) and preferable characteristics such as low format... | 10.1021/op0680136 | 0 |
A Practical Synthesis of <i>d</i>-α-Terpineol via Markovnikov Addition of <i>d</i>-Limonene Using Trifluoroacetic Acid | d -α-Terpineol ( 1 ), which is a useful flavor and fragrance compound, has been synthesized from d -limonene by Markovnikov addition using trifluoroacetic acid, followed by hydrolysis in 76% yield with 98% purity. | 10.1021/op068012d | 0 |
Safe Handling of Boranes at Scale | The safe handling of borane complexes and alkylboranes (trialkylboranes, dialkylboranes, and trialkylborohydride reagents) and related workup issues are addressed. Oxidation of alkylboranes and quenching of reaction mixtures to safely decompose the reagent or products are discussed. Several case studies demonstrate lar... | 10.1021/op068011l | 0 |
On the Synthesis of 1,1-Diamino-2,2-dinitroethene (FOX-7) by Nitration of 4,6-Dihydroxy-2-methylpyrimidine | The synthesis of 1,1-diamino-2,2-dinitroethene (FOX-7) by nitration of 4,6-dihydroxy-2-methylpyrimidine and hydrolysis of the resulting intermediate 2-dinitromethylene-5,5-dinitropyrimidine-4,6-dione has been studied. By varying the reaction parameters the optimal conditions for the synthesis of FOX-7 have been identif... | 10.1021/op068010t | 1 |
Efficient Synthesis of 3-Hydroxy-1,4-benzodiazepines Oxazepam and Lorazepam by New Acetoxylation Reaction of 3-Position of 1,4-Benzodiazepine Ring | Simple, efficient, and scalable syntheses of 3-hydroxy-1,4-benzodiazepines, oxazepam ( 1 ), and lorazepam ( 2 ) were developed. The syntheses are based on the new acetoxylation reaction of the 3-position of the 1,4-benzodiazepine ring. The reaction involves iodine (20−50 mol %)-catalyzed acetoxylation in the presence o... | 10.1021/op068009u | 1 |
Developing Processes for Crystallization-Induced Asymmetric Transformation | ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionDeveloping Processes for Crystallization-Induced Asymmetric TransformationN. G. AndersonCite this: Org. Process Res. Dev. 2006, 10, 3, 683Publication Date (Web):May 19, 2006Publication History Published online19 May 2006Published inissue 1 May 2006https://pubs.acs.org... | 10.1021/op068005p | 0 |
Recent Developments In Meerwein−Ponndorf−Verley and Related Reactions for the Reduction of Organic Functional Groups Using Aluminum, Boron, and Other Metal Reagents: A Review | ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTRecent Developments In Meerwein−Ponndorf−Verley and Related Reactions for the Reduction of Organic Functional Groups Using Aluminum, Boron, and Other Metal Reagents: A ReviewJin Soon ChaView Author Information Department of Chemistry, Yeungnam University, Gyongsan 712-749, Kor... | 10.1021/op068002c | 0 |
A Short and Efficient Synthesis of (<i>R</i>,<i>R</i>)-2-Methylcyclopropanecarboxylic Acid | We report herein a short and efficient synthesis of ( R, R )-2-methylcyclopropanecarboxylic acid via a Horner−Wadsworth−Emmons reaction involving commercially available ( S )-propylene oxide and triethylphosphonoacetate (TEPA). The TEPA/base/propylene oxide stoichiometry was found critical to achieve high yields. We th... | 10.1021/op060249m | 0 |
Preparation of 4-Vinylphenol Using pHCA Decarboxylase in a Two-Solvent Medium | An efficient synthesis of 4-vinylphenol (4-VP) from para -hydroxycinnamic acid (pHCA) that uses the enzyme para -hydroxycinnamic acid decarboxylase (PDC) in a two-phase aqueous−organic solvent has been developed. The 4-VP titer and catalyst productivity (17 g L - 1; 1010 g 4-VP isolated g - 1 catalyst) greatly exceed t... | 10.1021/op0602472 | 0 |
An Improved Synthesis of Memantine Hydrochloride: Anti-Alzheimer's Drug | An economical new process route has been developed for the large-scale synthesis of memantine hydrochloride ( 1 ) an anti-Alzheimer's drug. The procedure involves the conversion of 1,3-dimethyl adamantane ( 2 ) to formamide intermediate 8 as a key step, followed by hydrolysis to (1-amino-3,5-dimethyl adamantane) hydroc... | 10.1021/op060246+ | 0 |
Expedient Synthesis of MLN1251, A CCR5 Antagonist for Treatment of HIV | An expedient synthesis of MLN1251 has been developed that allows for the production of multikilogram quantities of the target compound. The key transformation is synthesis of a 5-hydroxyindole by a Nenitzescu reaction. The longest linear sequence is five steps with an overall yield of approximately 31%. | 10.1021/op060245h | 1 |
An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part II | The manufacturing process for lumefantrine, 2, one of the two active principles in the fixed-dose combination of the antimalarial drug Coartem, was reworked. For the conversion of 2-chloro-1-(2,7-dichloro-9H-fluoren-4-yl)ethanone, 5, to 2-dibutylamino-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol, 8, a one-pot process was de... | 10.1021/op060244p | 1 |
An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part I | Artemisinin and its derivatives, such as artemether, are highly sensitive compounds, which require careful optimized production processes for their manufacture. Due to robustness issues, the manufacturing procedure of the reduction of artemisinin with potassium borohydride to dihydroartemisinin was reinvestigated. The ... | 10.1021/op0602425 | 0 |
Development of a Concise Scaleable Synthesis of 2-Chloro-5-(pyridin-2-yl) Pyrimidine via a Negishi Cross-Coupling | A practical and scaleable synthesis of 2-chloro-5-(pyridin-2-yl) pyrimidine, an intermediate in the synthesis of a selective PDE-V inhibitor, was developed. A Negishi cross-coupling between the in situ prepared 2-pyridylzinc chloride and 5-iodo-2-chloropyrimidine catalyzed by Pd(PPh 3 ) 4 afforded the product in one st... | 10.1021/op060241c | 1 |
Practical Synthesis of 3-Amino-4,5-dimethylisoxazole from 2-Methyl-2-butenenitrile and Acetohydroxamic Acid | 3-Amino-4,5-dimethylisoxazole was prepared from technical-grade 2-methyl-2-butenenitrile and acetohydroxamic acid in a 62% overall yield on a multimole scale. The key features of this synthesis are (1) DBU treatment of the technical-grade nitrile mixture to provide a starting material of acceptable purity and (2) use o... | 10.1021/op060239l | 1 |
Practical Copper-Catalyzed Asymmetric Synthesis of Chiral Chrysanthemic Acid Esters | Practical copper salicylaldimine complex catalysts have been developed for the asymmetric synthesis of chiral chrysanthemic acid esters by the cyclopropanation reaction of 2,5-dimethyl-2,4-hexadiene with tert -butyl diazoacetate. First, the effects of the substituents on the salicylaldehyde moiety in the copper salicyl... | 10.1021/op060238t | 0 |
Dynamic Biphasic Counterion Exchange in a Configurationally Stable Aziridinium Ion: Efficient Synthesis and Isolation of a Koga C<sub>2</sub>-Symmetric Tetraamine Base | An efficient synthetic process for chiral tetraamine base ( R, R )- 5 is reported that leverages mechanistic understanding to enable control over key transformations. Specifically, a configurationally stable and observable aziridinium ion intermediate was found to undergo counterion exchange impacting the feasibility o... | 10.1021/op0602371 | 1 |
A Mixed-Ligand Approach Enables the Asymmetric Hydrogenation of an α-Isopropylcinnamic Acid en Route to the Renin Inhibitor Aliskiren | An asymmetric hydrogenation process for the α-isopropyl dihydrocinnamic acid derivative 2, an intermediate for the renin inhibitor aliskiren ( 4 ), has been developed using a rhodium catalyst ligated with a chiral monodentate phosphoramidite and a nonchiral phosphine. Whereas catalysts based on two equivalents of monod... | 10.1021/op0602369 | 0 |
Development of a Commercial Process to Produce Oxandrolone | A manufacturing scale process for the preparation of the anabolic steroid Oxandrolone was developed. Key elements included the following: the bromination of methylandrostanolone with perbromide to give the 2-bromoketone in ca. 80% yield with minimal dehydration, subsequent elimination of the bromide with Li 2 CO 3 /LiB... | 10.1021/op060231b | 1 |
A Facile Process for the Preparation of 2-Bromoethyl Methyl Ether | A convenient and large-scale synthesis of 2-bromoethyl methyl ether is described. | 10.1021/op060229k | 0 |
Development of a Large Scale Asymmetric Synthesis of Vanilloid Receptor (TRPV1) Antagonist ABT-102 | A highly efficient asymmetric synthesis of TRPV1 antagonist ABT-102 was developed and successfully demonstrated on a multi-kilogram scale. This process incorporates a new asymmetric synthesis of ( R )- tert -butylaminoindan, which is based on a chiral auxiliary induced diastereoselective reduction of its iminoindan pre... | 10.1021/op060228s | 1 |
Development of Practical Rhodium Phosphine Catalysts for the Hydrogenation of β-Dehydroamino Acid Derivatives | The rhodium-catalyzed asymmetric hydrogenation of various β-dehydroamino acid derivatives to give optically active β-amino acids has been examined. Chiral monodentate 4,5-dihydro-3 H -dinaphthophosphepines, which are easily tuned and accessible in a multi-10-g scale, have been used as ligands. The enantioselectivity is... | 10.1021/op0602270 | 0 |
Optimized Catalytic Enantioselective Aryl Transfer Process Gives Access to mGlu2 Receptor Potentiators | An asymmetric enantioselective aryl transfer reaction was developed to give access to the diarylmethanol 7 and ultimately acetate 2 which is useful for the preparation of mGlu2 receptor potentiators (Scheme 3). The aryl transfer chemistry involved the preparation of a proposed arylalkylzinc species 14 from boroxine 16 ... | 10.1021/op0602268 | 1 |
Design, Development, and Scale-Up of a Selective <i>meso</i>-Epoxide Desymmetrization Process | A pilot-plant scale desymmetrization of the cyclic meso -epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric... | 10.1021/op060225f | 1 |
Efficient Asymmetric Synthesis of <i>N</i>-[(1<i>R</i>)-6-Chloro-2,3,4,9-tetrahydro-1<i>H</i>-carbazol-1-yl]-2-pyridinecarboxamide for Treatment of Human Papillomavirus Infections | An efficient asymmetric synthesis of N -[(1 R )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazol-1-yl]-2-pyridinecarboxamide 1, a potential treatment for human papillomavirus infections, is described. The key step in the synthesis of this molecule is an asymmetric reductive amination directed by chiral (phenyl)ethylamines res... | 10.1021/op060223v | 1 |
Improved Process for Chloroxidation of Aryl Sulfides to Aryl Sulfonyl Chlorides in Commercial Grade Formic Acid | This paper discusses the process advantages of using commercial grade formic acid as the solvent for chlorine gas oxidation of aryl sulfides to sulfonyl chlorides. Compared to chloroxidation in methylene chloride, the chloroxidation in formic acid gave a consistently higher yield and easy product isolation for a sulfon... | 10.1021/op0602223 | 1 |
Development of an Asymmetric Acetate Aldol Reaction with a Trifluoromethyl Ketone | We describe the discovery and development of a chiral auxiliary-controlled asymmetric acetate aldol reaction with a trifluoromethyl ketone. Chiral acetate 3d was prepared efficiently from (1 S,2 R )-1-amino-2-indanol. Reaction of the lithium enolate of 3d with trifluoromethyl ketone 2 afforded aldol adducts in 95% HPLC... | 10.1021/op060211+ | 0 |
<i>N</i>,<i>N</i>-Diethyl-(<i>R</i>)-[3-(2-aminopropyl)-1<i>H</i>-indol-7-yloxy]acetamide: Its Process Chemistry Ranging from Enantiocontrolled Construction of the Chiral Amine Side Chain to Regioselective Functionalization of the Aromatic Starting Materials | To access N, N -diethyl-( R )-[3-(2-aminopropyl)-1 H -indol-7-yloxy]acetamide ( 3 ), a key intermediate for AJ-9677 ( 2 ) acting as a potent and selective agonist for β 3 -adrenergic receptors, the ( R )-configured 2-aminopropyl side chain of 3 is elaborated in three distinct ways: (1) chiral pool synthesis featuring t... | 10.1021/op060210h | 1 |
Enantioselective Synthesis of a Key Intermediate in a New Process for Orlistat Using Asymmetric Hydrogenation and a Grignard Reagent Promoted Lactone Cyclization | A new enantioselective synthesis of Orlistat suitable for large-scale preparation is described. Therein, the first isolated key intermediate ( R )-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2 H -pyran-2-one ( 12 ) is prepared via (a) the asymmetric hydrogenation of methyl 3-oxotetradecanoate to ( S )-3-hydroxytetradecanoa... | 10.1021/op060208q | 1 |
One-Pot Synthesis of 5-Methyl-3H-pyrrolo[2,3-<i>d</i>]pyrimidin-4(7H)-one | An efficient and environmentally benign synthesis of 5-methyl-3H-pyrrolo[2,3- d ]pyrimidin-4(7H)-one is described. An acyl-protected aminoacetone is reacted with cyanoacetamide to give 2-amino-4-methyl-1H-pyrrole-3-carboxamide, which is converted in one-pot to 5-methyl-3H-pyrrolo[2,3- d ]pyrimidin-4(7H)-one in 60% over... | 10.1021/op060207y | 1 |
Application of Band-Target Entropy Minimization to On-Line Raman Monitoring of an Organic Synthesis. An Example of New Technology for Process Analytical Technology | The hydrolysis of acetic anhydride to acetic acid in water as solvent was monitored by Raman microscopy. Both static and flow-through configurations were used in the experiments, and various experimental designs, i.e., multiple-experimental runs and multiple-perturbation semibatch mode, were considered. Various spectra... | 10.1021/op0602066 | 0 |
Development of a Scalable Synthesis of a Common Eastern Tricyclic Lactone for Construction of the Nodulisporic Acids | A scalable, second-generation synthesis of the densely functionalized eastern tricyclic lactone (+)- 6, a common intermediate, for construction of the nodulisporic acids has been achieved. Modifications to the first-generation route now permit access to (+)- 6 in 17 steps with an overall 16.5% yield. Key carbon−carbon ... | 10.1021/op060204l | 1 |
An Efficient and Impurity-Free Process for Telmisartan: An Antihypertensive Drug | Telmisartan ( 1 ), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan ( 1 ) suitable for large-scale production is described here by addressing various process development issues. The o... | 10.1021/op060200g | 1 |
An Efficient Synthesis of (<i>R</i>)-2-Butyl-3-hydroxypropionic Acid | An efficient synthesis of ( R )-2-butyl-3-hydroxypropionic acid ( 1 ) via a classical resolution of (±)-2-butyl-3-hydroxypropionic acid ( 7 ) with ( R )-α-methylbenzylamine is described. (±)-2-Butyl-3-hydroxypropionic acid ( 7 ) was readily available from diethyl butylmalonate ( 2 ) in two steps. Results on the enantio... | 10.1021/op060199l | 1 |
<i>SPECIAL FEATURE SECTION:</i> <u><i>SAFETY OF CHEMICAL PROCESSES</i></u> Safety HighlightsSafety Notables: Information from the Literature | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSES Safety HighlightsSafety Notables: Information from the LiteratureGerald A. Weisenburger and Paul F. VogtView Author Information Process Safety Laboratory, Pfizer, Inc., Groton, Connecticut 06340, U.S.A. E-mail: [email pr... | 10.1021/op060198t | 0 |
Reductive Carbonylation − an Efficient and Practical Catalytic Route for the Conversion of Aryl Halides to Aldehydes | Alternative routes for the introduction of aldehyde functionality are particularly desirable for fine chemical and pharmaceutical intermediates because of the wide range of further transformations that are possible. Catalytic processes are of particular interest for minimising waste, and therefore the reductive carbony... | 10.1021/op060193w | 0 |
Efficient Synthesis of (<i>S</i>)-2-(Cyclopentyloxycarbonyl)-amino-8-nonenoic Acid: Key Building Block for BILN 2061, an HCV NS3 Protease Inhibitor | A new procedure for the practical synthesis of ( S )-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid, a key building block for BILN 2061, an HCV NS3 protease inhibitor, has been developed. The key step features a kinetic resolution of racemic 2-acetylamino-8-nonenoic acid with acylase I. In addition, the undesired ( R ... | 10.1021/op0601924 | 1 |
An Improved Manufacturing Process for Fluvastatin | An improved manufacturing process for fluvastatin 1 has been developed by performing the condensation reaction of E -[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenal, 4, with the dianion of tert -butyl acetoacetate and the subsequent low-temperature reduction to 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H... | 10.1021/op060191b | 1 |
Synthesis of 4-Fluoro-β-(4-fluorophenyl)-<scp>l</scp>-phenylalanine by an Asymmetric Phase-Transfer Catalyzed Alkylation: Synthesis on Scale and Catalyst Stability | 4-Fluoro-β-(4-fluorophenyl)- l -phenylalanine 1 was synthesized by the asymmetric phase-transfer catalyzed alkylation of tert -butyl glycinate-benzophenone Schiff base using the cinchona alkaloid derived catalyst 6 . Upon scaling, it was observed that to achieve high levels of enantioselectivity, it was necessary to ad... | 10.1021/op060190j | 0 |
Suppression of a Palladium-Mediated Homocoupling in a Suzuki Cross-Coupling Reaction. Development of an Impurity Control Strategy Supporting Synthesis of LY451395 | Described herein is the development of a control strategy resulting in exclusion of a persistent impurity ( 6 ) formed by a palladium (II)-mediated homocoupling of boronic acid ( 3 ) during a Suzuki cross-coupling reaction. Nearly complete suppression of the undesired homocoupling reaction was achieved through two proc... | 10.1021/op060180i | 1 |
Synthesis of Naturally Occurring Nitrogen Heterocycles from Carbohydrates By El Sayed H. El Ashry and Ahmed El Nemr. Blackwell Publishing: Oxford. 2005. 443 pp. £119. ISBN 1-4051-2934-4. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewSynthesis of Naturally Occurring Nitrogen Heterocycles from Carbohydrates By El Sayed H. El Ashry and Ahmed El Nemr. Blackwell Publishing: Oxford. 2005. 443 pp. £119. ISBN 1-4051-2934-4.W. J. WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfie... | 10.1021/op060174m | 0 |
Scale-Up of the Green Synthesis of Azacycloalkanes and Isoindolines under Microwave Irradiation | A green approach to N- heterocyclization reactions ranging in scale from 20 mmol to 1 mol performed under microwave irradiation in open vessels has been investigated. By using water as the solvent and no transition metal catalysts, N -heterocycles are formed in a fraction of the time needed for conventional synthesis o... | 10.1021/op0601722 | 0 |
A Concise Synthesis of Racemic 1-(6,7-Dimethoxy-2-naphthyl)-1-(1 <i>H</i> -imidazol-4-yl)-2-methylpropan-1-ol for a Potent C <sub>17</sub> , <sub>20</sub> -Lyase Inhibitor | The development of a practical and scaleable synthesis of 1-(6,7-dimethoxy-2-naphthyl)-1-(1 H -imidazol-4-yl)-2-methylpropan-1-ol ( 2 ) is described. Racemate 2 was synthesized from commercially available 4(5)-imidazolecarboxyaldehyde ( 7 ) in three steps excluding chromatography. 4(5)-Cyanoimidazole ( 10 ) was prepare... | 10.1021/op060171+ | 1 |
What Type of Reactions Do Process Chemists Use on Scale? | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTWhat Type of Reactions Do Process Chemists Use on Scale?Trevor LairdView Author Information EditorCite this: Org. Process Res. Dev. 2006, 10, 5, 851–852Publication Date (Web):August 17, 2006Publication History Published online17 August 2006Published inissue 1 September 2006http... | 10.1021/op060164l | 0 |
Process Development and Scale-up of <b>AG035029</b> | A practical process for the synthesis of PPARγ agonist AG035029 was developed which involved six steps along the longest linear path. The process development utilized automated technology and computational chemistry extensively to accelerate the speed of the project in the areas of catalyst screening, reaction optimiza... | 10.1021/op0601621 | 1 |
Enantioselective Ketone Hydrogenation: From R&D to Pilot Scale with Industrially Viable Ru/Phosphine−Oxazoline Complexes | The development of a pilot process for the enantioselective hydrogenation of 3,5-bistrifluoromethyl acetophenone (BTMA) using a Ru/phosphine−oxazoline complex in toluene in the presence of aqueous NaOH is described. Various reaction parameters and quality risk factors such as ligand structure, substrate quality, reacti... | 10.1021/op0601619 | 0 |
DMSO Can Be More than a Solvent: Thermal Analysis of Its Chemical Interactions with Certain Chemicals at Different Process Stages | During the process development of the product 6 via the route presented in Scheme 1, we encountered several safety issues that had to be resolved before moving these stages to production. In each case, the safety issues are related to the interaction of the solvent used, DMSO (dimethylsulphoxide, 3 ), with one of the o... | 10.1021/op060158p | 1 |
Expeditious Process Improvement for the Synthesis of RWJ-333966 | We improved chemical processes for synthesizing RWJ-333966 1 and obtained this compound over five steps in 40% overall yield. | 10.1021/op0601565 | 1 |
Application of the Tisler Triazolopyrimidine Cyclization to the Synthesis of a Crop Protection Agent and an Intermediate | A new synthetic route to the Dow AgroSciences early stage sulfonamide herbicide 3-(2-methoxy-4-trifluoromethyl)- N -(5,7-dimethoxy[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl)pyridinesulfonamide (pyroxsulam) has been developed. The synthesis is based on formation of the triazole ring as the final step, utilizing the Tisler t... | 10.1021/op0601518 | 1 |
Development of Large-Scale Preparations of Indole Derivatives: Evaluation of Potential Thermal Hazards and Studies of Reaction Kinetics and Mechanisms | Hydrogenation of ( E )-2-nitropyrrolidinostyrene in the presence of the doped rhodium catalyst is safe, scalable, and highly effective for the preparation of 6-benzyloxyindole. Reaction kinetics with/without additives also were examined using in situ IR for the first time. Results showed that the additives decelerate t... | 10.1021/op060150f | 0 |
Beating the Hydrogen Bond: First Selective and High-Yielding<i>N</i>-Acylation Process for an α,β-Diaminoalcohol | The first selective and high-yielding N -acylation of an α,β-diaminoalcohol is reported, as well as the first use as N -acylation agent of a S -mercaptobenzothiazolyl thioester of an α,β-unsaturated carboxylic acid. Other conventional coupling methods (acid chloride, uronium salt, carbonyl diimidazole, phosphonium salt... | 10.1021/op0601464 | 1 |
Process Safety Evaluation of a Magnesium−Iodine Exchange Reaction | An unexpected highly exothermic decomposition was observed during routine safety analysis of the magnesium−iodine exchange reaction of 2-iodo-4-fluorotoluene ( 3 ) with commercially available i -PrMgCl (2.0 M solution in THF). When the reaction mixture was scanned in an adiabatic calorimeter with the use of a 2 °C/min ... | 10.1021/op060145b | 0 |
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