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Search for "active pharmaceutical ingredient" in Full Text gives 12 result(s) in Beilstein Journal of Organic Chemistry.
Mechanochemical amorphization of chitin: impact of apparatus material on performance and contamination
- Thomas Di Nardo and
- Audrey Moores
Beilstein J. Org. Chem. 2019, 15, 1217–1225, doi:10.3762/bjoc.15.119
- siliceous rock against pyrite [2][3]. Mechanochemistry comes with intrinsic advantages associated with the lack of solvent use during reaction, thus largely reducing the generation of waste [4] even in active pharmaceutical ingredient synthesis [5]. Yet mechanochemistry also allows the production of novel
Graphical Abstract
Figure 1: CrI% for chitin samples, before and after milling in a jar with one ball made of SS, ZrO2, Cu, Al, ...
Figure 2: Value of CrI after milling as a function of the Vickers hardness values of the media (Jar and ball)...
Figure 3: Crystallinity index (%) after milling as a function of frequency. ZrO2 and SS jars are compared, bo...
Figure 4: Crystallinity index (%) of chitin milled with 9.5 mm balls of PTFE, ZrO2 and SS each used in jars o...
Figure 5: Correlation between the ball mass (orange line) or kinetic energy (blue line) with the crystallinit...
Figure 6: Metal contamination of milled chitin determined by ICP–OES, as a function of the milling medium. Th...
Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry
- Michael K. Bogdos,
- Emmanuel Pinard and
- John A. Murphy
Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179
- is provided and the reaction demonstrates reasonable regioselectivity (6.5:1). The synthesis of 15c, a precursor to an active pharmaceutical ingredient (API), by the authors demonstrates how this method is immediately useful in the synthesis of biologically active molecules. Although the authors
Graphical Abstract
Figure 1: Depiction of the energy levels of a typical organic molecule and the photophysical processes it can...
Figure 2: General catalytic cycle of a photocatalyst in a photoredox organocatalysed reaction. [cat] – photoc...
Figure 3: Structures and names of the most common photocatalysts encountered in the reviewed literature.
Figure 4: General example of a reductive quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocata...
Figure 5: General example of an oxidative quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocat...
Scheme 1: Oxidative coupling of aldehydes and amines to amides using acridinium salt photocatalysis.
Figure 6: Biologically active molecules containing a benzamide linkage.
Scheme 2: The photocatalytic reduction of amino acids to produce the corresponding free or protected amines.
Scheme 3: The organocatalysed photoredox base-mediated oxidation of thiols to disulfides.
Scheme 4: C-Terminal modification of peptides and proteins using organophotoredox catalysis.
Scheme 5: The reduction and aryl coupling of aryl halides using a doubly excited photocatalyst (PDI).
Figure 7: Mechanism for the coupling of aryl halides using PDI, which is excited sequentially by two photons.
Scheme 6: The arylation of five-membered heteroarenes using arenediazonium salts under organophotoredox condi...
Scheme 7: The C–H (hetero)arylation of five-membered heterocycles under Eosin Y photocatalysis.
Scheme 8: The C–H sulfurisation of imidazoheterocycles using Eosin B-catalyzed photochemical methods.
Scheme 9: The introduction of the thiocyanate group using Eosin Y photocatalysis.
Scheme 10: Sulfonamidation of pyrroles using oxygen as the terminal oxidant.
Scheme 11: DDQ-catalysed C–H amination of arenes and heteroarenes.
Scheme 12: Photoredox-promoted radical Michael addition reactions of allylic or benzylic carbons.
Figure 8: Proposed mechanistic rationale for the observed chemoselectivities.
Scheme 13: The photocatalytic manipulation of C–H bonds adjacent to amine groups.
Scheme 14: The perylene-catalysed organophotoredox tandem difluoromethylation–acetamidation of styrene-type al...
Figure 9: Examples of biologically active molecules containing highly functionalised five membered heterocycl...
Scheme 15: The [3 + 2]-cycloaddition leading to the formation of pyrroles, through the reaction of 2H-azirines...
Figure 10: Proposed intermediate that determines the regioselectivity of the reaction.
Figure 11: Comparison of possible pathways of reaction and various intermediates involved.
Scheme 16: The acridinium salt-catalysed formation of oxazoles from aldehydes and 2H-azirines.
Scheme 17: The synthesis of oxazolines and thiazolines from amides and thioamides using organocatalysed photor...
Figure 12: Biologically active molecules on the market containing 1,3,4-oxadiazole moieties.
Scheme 18: The synthesis of 1,3,4-oxadiazoles from aldehyde semicarbazones using Eosin Y organophotocatalysis.
Scheme 19: The dimerization of primary thioamides to 1,2,4-thiadiazoles catalysed by the presence of Eosin Y a...
Scheme 20: The radical cycloaddition of o-methylthioarenediazonium salts and substituted alkynes towards the f...
Scheme 21: The dehydrogenative cascade reaction for the synthesis of 5,6-benzofused heterocyclic systems.
Figure 13: Trifluoromethylated version of compounds which have known biological activities.
Scheme 22: Eosin Y-catalysed photoredox formation of 3-substituted benzimidazoles.
Scheme 23: Oxidation of dihydropyrimidines by atmospheric oxygen using photoredox catalysis.
Scheme 24: Photoredox-organocatalysed transformation of 2-substituted phenolic imines to benzoxazoles.
Scheme 25: Visible light-driven oxidative annulation of arylamidines.
Scheme 26: Methylene blue-photocatalysed direct C–H trifluoromethylation of heterocycles.
Scheme 27: Photoredox hydrotrifluoromethylation of terminal alkenes and alkynes.
Scheme 28: Trifluoromethylation and perfluoroalkylation of aromatics and heteroaromatics.
Scheme 29: The cooperative asymmetric and photoredox catalysis towards the functionalisation of α-amino sp3 C–...
Scheme 30: Organophotoredox-catalysed direct C–H amidation of aromatics.
Scheme 31: Direct C–H alkylation of heterocycles using BF3K salts. CFL – compact fluorescent lamp.
Figure 14: The modification of camptothecin, demonstrating the use of the Molander protocol in LSF.
Scheme 32: Direct C–H amination of aromatics using acridinium salts.
Scheme 33: Photoredox-catalysed nucleophilic aromatic substitution of nucleophiles onto methoxybenzene derivat...
Scheme 34: The direct C–H cyanation of aromatics with a focus on its use for LSF.
Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds
- Santanu Hati,
- Ulrike Holzgrabe and
- Subhabrata Sen
Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162
- active pharmaceutical ingredient (API). This further establishes oxidative dehydrogenation as an impactful strategy in the repertoire of organic synthesis (Scheme 40). The next example demonstrates the process of oxidative dehydrogenation in the synthesis of bioactive natural products. Accordingly, Stahl
Graphical Abstract
Figure 1: Representative bioactive heterocycles.
Scheme 1: The concept of oxidative dehydrogenation.
Scheme 2: IBX-mediated oxidative dehydrogenation of various heterocycles [31-34].
Scheme 3: Potential mechanism of IBX-mediated oxidative dehydrogenation of N-heterocycles [31-34].
Scheme 4: IBX-mediated room temperature one-pot condensation–oxidative dehydrogenation of o-aminobenzylamines....
Scheme 5: Anhydrous cerium chloride-catalyzed, IBX-mediated oxidative dehydrogenation of various heterocycles...
Scheme 6: Oxidative dehydrogenation of quinazolinones with I2 and DDQ [37-40].
Scheme 7: DDQ-mediated oxidative dehydrogenation of thiazolidines and oxazolidines.
Scheme 8: Oxone-mediated oxidative dehydrogenation of intermediates from o-phenylenediamine and o-aminobenzyl...
Scheme 9: Transition metal-free oxidative cross-dehydrogenative coupling.
Scheme 10: NaOCl-mediated oxidative dehydrogenation.
Scheme 11: NBS-mediated oxidative dehydrogenation of tetrahydro-β-carbolines.
Scheme 12: One-pot synthesis of various methyl(hetero)arenes from o-aminobenzamide in presence of di-tert-buty...
Scheme 13: Oxidative dehydrogenation of 1, 4-DHPs.
Scheme 14: Synthesis of quinazolines in the presence of MnO2.
Scheme 15: Selenium dioxide and potassium dichromate-mediated oxidative dehydrogenation of tetrahydro-β-carbol...
Scheme 16: Synthesis of substituted benzazoles in the presence of barium permanganate.
Scheme 17: Oxidative dehydrogenation with phenanthroline-based catalysts. PPTS = pyridinium p-toluenesulfonic ...
Scheme 18: Oxidative dehydrogenation with Flavin mimics.
Scheme 19: o-Quinone based bioinspired catalysts for the synthesis of dihydroisoquinolines.
Scheme 20: Cobalt-catalyzed aerobic dehydrogenation of Hantzch 1,4-DHPs and pyrazolines.
Scheme 21: Mechanism of cobalt-catalyzed aerobic dehydrogenation of Hantzch 1,4-DHPs.
Scheme 22: DABCO and TEMPO-catalyzed aerobic oxidative dehydrogenation of quinazolines and 4H-3,1-benzoxazines....
Scheme 23: Putative mechanism for Cu(I)–DABCO–TEMPO catalyzed aerobic oxidative dehydrogenation of tetrahydroq...
Scheme 24: Potassium triphosphate modified Pd/C catalysts for the oxidative dehydrogenation of tetrahydroisoqu...
Scheme 25: Ruthenium-catalyzed polycyclic heteroarenes.
Scheme 26: Plausible mechanism of the ruthenium-catalyzed dehydrogenation.
Scheme 27: Bi-metallic platinum/iridium alloyed nanoclusters and 5,5’,6,6’-tetrahydroxy-3,3,3’,3’-tetramethyl-...
Scheme 28: Magnesium iodide-catalyzed synthesis of quinazolines.
Scheme 29: Ferrous chloride-catalyzed aerobic dehydrogenation of 1,2,3,4-tetrahydroquinolines.
Scheme 30: Cu(I)-catalyzed oxidative aromatization of indoles.
Scheme 31: Putative mechanism of the transformation.
Scheme 32: Oxidative dehydrogenation of pyrimidinones and pyrimidines.
Scheme 33: Putative mechanisms (radical and metal-catalyzed) of the transformation.
Scheme 34: Ferric chloride-catalyzed, TBHP-oxidized synthesis of substituted quinazolinones and arylquinazolin...
Scheme 35: Iridium-catalyzed oxidative dehydrogenation of quinolines.
Scheme 36: Microwave-assisted synthesis of β-carboline with a catalytic amount of Pd/C in lithium carbonate at...
Scheme 37: 4-Methoxy-TEMPO-catalyzed aerobic oxidative synthesis of 2-substituted benzazoles.
Scheme 38: Plausible mechanism of the 4-methoxy-TEMPO-catalyzed transformation.
Scheme 39: One-pot synthesis of 2-arylquinazolines, catalyzed by 4-hydroxy-TEMPO.
Scheme 40: Oxidative dehydrogenation – a key step in the synthesis of AZD8926.
Scheme 41: Catalytic oxidative dehydrogenation of tetrahydroquinolines to afford bioactive molecules.
Scheme 42: Iodobenzene diacetate-mediated synthesis of β-carboline natural products.
Dynamics and interactions of ibuprofen in cyclodextrin nanosponges by solid-state NMR spectroscopy
- Monica Ferro,
- Franca Castiglione,
- Nadia Pastori,
- Carlo Punta,
- Lucio Melone,
- Walter Panzeri,
- Barbara Rossi,
- Francesco Trotta and
- Andrea Mele
Beilstein J. Org. Chem. 2017, 13, 182–194, doi:10.3762/bjoc.13.21
- active pharmaceutical ingredient (API) entrapped in a polymeric scaffold. The results pointed out that the motion of a small drug molecule drastically changes from subdiffusive to slightly superdiffusive regimes depending on the cyclodextrin to CL molar ratio, and hence on the CDNS polymeric structure
Graphical Abstract
Figure 1: Schematic thermodynamic description of the CP process and time constants. The I-S model (left), the ...
Figure 2: 1H MAS NMR spectra of a) CDNS(1:8)-IbuNa and b) CDNS(1:8). The inset (top right) shows the expansio...
Figure 3: The effect of the spinning speed on the spectral features. 1H MAS NMR spectra of a) CDNS(1:4)-IbuNa...
Figure 4: 13C CP-MAS NMR spectra for samples of β-CD (top), CDNS(1:4) (middle) and CDNS(1:8) polymers (bottom...
Figure 5: 13C CP-MAS NMR spectrum of: a) CDNS(1:4) polymer; b) CDNS(1:4)-IbuNa system; c) CDNS(1:8)-IbuNa sys...
Figure 6: 13C CP-MAS NMR spectra of CDNS(1:4) acquired with CP variable contact time in the range 50 μs–7 ms.
Figure 7: Time dependence of 13C magnetization for CDNS(1:4) (left) and CDNS(1:8) (right) polymers.
Figure 8: 1H-13C CP oscillatory kinetics for the carbon C(1) and C(4) of CDNS(1:4)-IbuNa sample (left) and CD...
Figure 9: 1H-13C CP oscillatory kinetics for the ibuprofen aromatic carbon atoms C(6,8) in samples CDNS(1:4)-...
Figure 10: PXRD patterns of: a) CDNS(1:8), b) CDNS(1:4), c) CDNS(1:8)-IbuNa loaded, d) CDNS(1:4)-IbuNa loaded,...
Extrusion – back to the future: Using an established technique to reform automated chemical synthesis
- Deborah E. Crawford
Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9
- compound or active pharmaceutical ingredient (API) synthesis in this industry. There has been some research in the last decade demonstrating the preparation of cocrystals by hot melt extrusion (HME) and liquid assisted extrusion. This work has been essentially conducted by Amgen, preparing cocrystals
Graphical Abstract
Figure 1: Typical pilot scale single screw extruder (left) and a laboratory scale twin screw extruder (right)....
Figure 2: PTFE screw employed in single screw extrusion, with increasing root diameter (RD) from 45 mm to 95 ...
Figure 3: Modulated stainless steel intermeshing co-rotating screws employed typically in twin screw extrusio...
Scheme 1: Polymerisation of styrene using s-BuLi as an initiator.
Scheme 2: Telescoping process of the formation of polystyrene, followed by post polymerisation functionalisat...
Scheme 3: Proposed mechanism for the branching of polylactide. Adapted from [23].
Scheme 4: Chemical reaction between isocyanate and an alcohol to form polyurethane.
Figure 4: Representative diagram explaining the process involved in step growth polymerisation, which involve...
Scheme 5: Generic polycondensation reaction to produce polyamides.
Figure 5: Comparison of choline chloride/D-fructose DES prepared via twin screw extrusion (left) and conventi...
Scheme 6: Synthesis of HKUST-1, ZIF-8 and Al(fumarate)OH by twin screw extrusion. Adapted from [2].
Figure 6: Synthesis of Ni(NCS)2(PPh3)2 and [Ni(salen)] by twin screw extrusion. Adapted from [2].
Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins
- Andrea Mascitti,
- Massimiliano Lupacchini,
- Ruben Guerra,
- Ilya Taydakov,
- Lucia Tonucci,
- Nicola d’Alessandro,
- Frederic Lamaty,
- Jean Martinez and
- Evelina Colacino
Beilstein J. Org. Chem. 2017, 13, 19–25, doi:10.3762/bjoc.13.3
- preparation of an active pharmaceutical ingredient (API), the anticonvulsant drug ethotoin 7 [9] (marketed as Peganone®, Scheme 1). We describe herein the impact of the addition of variable amounts of PEG, PEG chain length and end terminal groups, for the preparation of diverse 3,5-disubstituted hydantoins
Graphical Abstract
Scheme 1: PEG-assisted grinding strategy for the preparation of 3,5-disubstituted hydantoins.
Release of β-galactosidase from poloxamine/α-cyclodextrin hydrogels
- César A. Estévez,
- José Ramón Isasi,
- Eneko Larrañeta and
- Itziar Vélaz
Beilstein J. Org. Chem. 2014, 10, 3127–3135, doi:10.3762/bjoc.10.330
- , first order, and Hopfenberg. Korsmeyer developed a simple formula to describe the release of the active pharmaceutical ingredient (API) from a polymeric system. They found that this model is acceptable up to an amount of 60% of API released. The exponent of the power law indicates the release mechanism
Graphical Abstract
Figure 1: Inclusion complex (polypseudorotaxane) between α-cyclodextrins and reverse Tetronics.
Figure 2: 90R4/α-CD gels loaded with lactase. Octablock Tetronic molecules (grey) are threaded by CDs (red) f...
Figure 3: FTIR spectra of Tetronic 90R4, α-CD, lactase and T25a10 complex.
Figure 4: Release profiles of lactase from T25a10 (open circles) and T15a10 (filled circles) at pH 6 from a) ...
Figure 5: Contribution of diffusion (open circles) and erosion (filled circles) mechanisms from polymers a) T...
Figure 6: Chemical structure of a reverse Tetronic.
Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs
- Lisa F. Becker,
- Dennis H. Schwarz and
- Gerhard Wenz
Beilstein J. Org. Chem. 2014, 10, 2920–2927, doi:10.3762/bjoc.10.310
- anaesthesia. Keywords: active pharmaceutical ingredient; binding constant; cyclodextrin; derivatization; gas chromatography; sevoflurane; substitution pattern; Introduction Cyclodextrins (CDs) are cyclic oligomers of α-1,4-linked glucose units. Those CDs consisting of 6, 7, and 8 glucose units are called α
Graphical Abstract
Scheme 1: Synthetic route to neutral water-soluble CD thioethers.
Figure 1: ESI MS spectra of CD derivatives 2b1 (left) and 3b1 (right).
Figure 2: 1H NMR spectra of a) the statistical CD derivatives 2b1 and b) the corresponding uniform derivative ...
Figure 3: Transmission (λ = 670 nm) of aqueous solutions (1.0 wt %) of 2b1 (red) and 3b1 (blue).
Figure 4: Decay of the relative vapour pressure A/A0 as function of the host concentration 3b1 measured by GC...
Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine
- Ashley R. Longstreet,
- Suzanne M. Opalka,
- Brian S. Campbell,
- B. Frank Gupton and
- D. Tyler McQuade
Beilstein J. Org. Chem. 2013, 9, 2570–2578, doi:10.3762/bjoc.9.292
- of the active pharmaceutical ingredient (API) (analysis will be included on future publications). We hypothesized that by both reducing the cost of goods via chemistry changes and reducing the unit operations the most significant cost reduction could be achieved. Herein, we demonstrate a proof of
- improvements, we suggest that a commercial version of this process must address how to achieve long-term stability at the higher concentrations. Creating a chemical process for an active pharmaceutical ingredient is a careful integration of chemical and regulatory challenges. While from an academic standpoint
Graphical Abstract
Figure 1: The estimated demand of for nevirapine until 2015 [6].
Scheme 1: Commercial building blocks to nevirapine.
Scheme 2: a) Current commercial process to CAPIC and b) newly developed batch synthesis to CAPIC and its brom...
Scheme 3: Proposed synthesis to 2-bromo-4-methylnicotinonitrile using a continuous approach with the consider...
Figure 2: a) Flow scheme to produce the enamine intermediate 5 from isopropylidenemalononitrile (4) (see Supporting Information File 1 for...
Scheme 4: Flow scheme to produce the enamine 5 starting from acetone and malononitrile (See Supporting Information File 1 for details).
Figure 3: Comparing the long-term stability of the Al2O3 and 3 Å MS columns when the Al2O3 column temperature...
Scheme 5: Several byproducts were observed when producing 5 starting from acetone and malononitrile. 7 is for...
Scheme 6: Flow scheme to produce 2-bromo-4-methylnicotinonitrile (6b) in 81% yield from 4 with a 1 M concentr...
Scheme 7: Reactor scheme for the continuous synthesis of 2-bromo-4-methylnicotinonitrile (6b) with an average...
A novel asymmetric synthesis of cinacalcet hydrochloride
- Veera R. Arava,
- Laxminarasimhulu Gorentla and
- Pramod K. Dubey
Beilstein J. Org. Chem. 2012, 8, 1366–1373, doi:10.3762/bjoc.8.158
- (CNC·HCl, 1, Figure 1) is the first active pharmaceutical ingredient (API) approved by the USFDA for the treatment of secondary hyperparathyroidism. It is sold under the trade names of Sensipar® in USA and Mimpara® in Europe. Hyperparathyroidism (HPT) is a condition characterized by the over-secretion of
Graphical Abstract
Figure 1: Cinalcet hydrochloride (CNC·HCl, 1).
Scheme 1: Asymmetric synthesis of 1.
Scheme 2: Synthesis of the intermediates 5 and 6 from 8.
Scheme 3: Asymmetric synthesis of naphthylethylsulfinamide 4.
Scheme 4: Conversion of 8 to 10.
Scheme 5: Synthesis of alcohol intermediate 12 from 10.
Scheme 6: Synthesis of bromo 5 and iodo 6 derivatives.
Scheme 7: Regioselective N-alkylation of naphthyl ethyl sulfinamide 4a.
Scheme 8: Acid hydrolysis of N-tert-butanesulfinyl group in 7.
An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
- Marcus Baumann,
- Ian R. Baxendale,
- Steven V. Ley and
- Nikzad Nikbin
Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57
Graphical Abstract
Figure 1: Structures of atorvastatin and other commercial statins.
Figure 2: Structure of compactin.
Scheme 1: Synthesis of pentasubstituted pyrroles.
Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
Scheme 6: Convergent synthesis towards atorvastatin.
Figure 3: Binding pocket of sunitinib in the TRK KIT.
Scheme 7: Synthesis of sunitinib.
Scheme 8: Alternative synthesis of sunitinib.
Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
Scheme 13: Alternative introduction of the sulfonamide.
Scheme 14: Negishi-type coupling to benzylic sulfonamides.
Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
Scheme 18: Improved synthesis of rizatriptan.
Scheme 19: Larock-type synthesis of rizatriptan.
Scheme 20: Synthesis of eletriptan.
Scheme 21: Heck coupling for the indole system in eletriptan.
Scheme 22: Attempted Fischer indole synthesis of elatriptan.
Scheme 23: Successful Fischer indole synthesis for eletriptan.
Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
Scheme 26: Palladium-mediated synthesis of ondansetron.
Scheme 27: Fischer indole synthesis of ondansetron.
Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
Figure 4: Structures of carvedilol 136 and propranolol 137.
Scheme 29: Synthesis of the carbazole core of carvedilol.
Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
Scheme 31: Convergent synthesis of etodolac.
Scheme 32: Alternative synthesis of etodolac.
Figure 5: Structures of imidazole-containing drugs.
Scheme 33: Synthesis of functionalised imidazoles towards losartan.
Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
Scheme 35: Synthesis of trisubstituted imidazoles.
Scheme 36: Preparation of the imidazole ring in olmesartan.
Scheme 37: Synthesis of ondansetron.
Scheme 38: Alternative route to ondansetron and its analogues.
Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
Scheme 40: Synthesis of benzimidazole core pantoprazole.
Figure 6: Structure of rabeprazole 194.
Scheme 41: Synthesis of candesartan.
Scheme 42: Alternative access to the candesartan key intermediate 216.
Scheme 43: .Medicinal chemistry route to telmisartan.
Scheme 44: Improved synthesis of telmisartan.
Scheme 45: Synthesis of zolpidem.
Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
Figure 7: Structure of celecoxib.
Scheme 47: Preparation of celecoxib.
Scheme 48: Alternative synthesis of celecoxib.
Scheme 49: Regioselective access to celecoxib.
Scheme 50: Synthesis of pazopanib.
Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
Scheme 52: Regioselective synthesis of anastrozole.
Scheme 53: Triazine-mediated triazole formation towards anastrozole.
Scheme 54: Alternative routes to 1,2,4-triazoles.
Scheme 55: Initial synthetic route to sitagliptin.
Figure 8: Binding of sitagliptin within DPP-IV.
Scheme 56: The process route to sitagliptin key intermediate 280.
Scheme 57: Synthesis of maraviroc.
Scheme 58: Synthesis of alprazolam.
Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
Scheme 60: Synthesis of itraconazole.
Scheme 61: Synthesis of rufinamide.
Scheme 62: Representative tetrazole formation in valsartan.
Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
Scheme 63: Early stage introduction of the tetrazole in losartan.
Scheme 64: Synthesis of cilostazol.
Figure 11: Structure of cefdinir.
Scheme 65: Semi-synthesis of cefdinir.
Scheme 66: Thiazole syntheses towards ritonavir.
Scheme 67: Synthesis towards pramipexole.
Scheme 68: Alternative route to pramipexole.
Scheme 69: Synthesis of famotidine.
Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
Scheme 71: Synthesis of ziprasidone.
Figure 12: Structure of mometasone.
Scheme 72: Industrial access to 2-furoic acid present in mometasone.
Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
Scheme 74: Synthesis of nitrofurantoin.
Scheme 75: Synthesis of benzofuran.
Scheme 76: Synthesis of amiodarone.
Scheme 77: Synthesis of raloxifene.
Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
Scheme 79: Gewald reaction in the synthesis of olanzapine.
Scheme 80: Alternative synthesis of olanzapine.
Figure 13: Access to simple thiophene-containing drugs.
Scheme 81: Synthesis of clopidogrel.
Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
Scheme 83: Alternative synthesis of key intermediate 422.
Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
Scheme 84: Synthesis of timolol.
Scheme 85: Synthesis of tizanidine 440.
Scheme 86: Synthesis of leflunomide.
Scheme 87: Synthesis of sulfamethoxazole.
Scheme 88: Synthesis of risperidone.
Figure 15: Relative abundance of selected transformations.
Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
Identification and synthesis of impurities formed during sertindole preparation
- I. V. Sunil Kumar,
- G. S. R. Anjaneyulu and
- V. Hima Bindu
Beilstein J. Org. Chem. 2011, 7, 29–33, doi:10.3762/bjoc.7.5
- ) was <0.05% [10]. Conclusion For the better understanding of the synthetic pathway of an active pharmaceutical ingredient (API) it is necessary to identify all the impurities formed/anticipated. In this regard we have synthesized and characterized different potential process-related impurities of
Graphical Abstract
Figure 1: Sertindole (1), process related impurities and metabolites.
Scheme 1: Reagents and conditions: i) K2CO3, CuBr, ethylenediamine, DMF 130–135 °C; ii) CH3COOH, CF3COOH, 100...
Scheme 2: Reagents, conditions (and yields): i) (a) pH adjusted to 6; (b) Pd/C, HCOONH4, AcOH, MeOH, reflux (...
Scheme 3: Reagents, conditions (and yields): i) 16, K2CO3, KI, MIBK, reflux (73.9%).
Scheme 4: Reagents, conditions (and yields): i) Cs2CO3, DMF, 130–135 °C; ii) 14, CH3COOH, CF3COOH, 100–105 °C...
Scheme 5: Reagents, conditions (and yields): i) (a) pH adjusted to 6–7; (b) H2, PtO2, MeOH, AcOH, 30–35 °C (7...
Scheme 6: Reagents, conditions (and yields): i) 12, K2CO3, Cu(II)Br, ethylenediamine, DMF, 130–135 °C, (51%);...
Scheme 7: Reagents, conditions (and yield): i) (a) 16, Et3N, NaI, CH3CN, reflux; (b) column chromatography (1...
Scheme 8: Reagents, conditions (and yield): i) (a) mCPBA, MeOH, 40–45 °C; (b) column chromatography (52.2%).
