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Search for "atorvastatin" in Full Text gives 10 result(s) in Beilstein Journal of Organic Chemistry.
An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides
- Shubham Sharma,
- Dharmender Singh,
- Sunit Kumar,
- Vaishali,
- Rahul Jamra,
- Naveen Banyal,
- Deepika,
- Chandi C. Malakar and
- Virender Singh
Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22
- linkage is present in several naturally occurring compounds and it is also one of the most productive functional groups in current pharmaceutical drugs [50][51]. As prime examples; atorvastatin [52], valsartan [53] and N-cyclohexylethyl-ETAsV are successfully utilized to treat various life challenging
Graphical Abstract
Figure 1: Representative drug molecules based on pyrazole, thioamide, and amide derivatives.
Figure 2: Previous and present findings for the synthesis of thioamide derivatives.
Scheme 1: Synthesis of pyrazole C-3-tethered thioamides.
Scheme 2: Synthesis of pyrazole C-4-tethered thioamides.
Scheme 3: Metal- and catalyst-free preparation of pyrazole C-5-linked thioamide conjugates.
Scheme 4: Synthesis of 4-iodopyrazole C-3-tethered thioamides.
Scheme 5: Gram-scale scope of the current protocol.
Scheme 6: Control experiment.
Scheme 7: H2O2-mediated synthesis of pyrazole-pyridine conjugates with amide tethers.
Scheme 8: Synthesis of pyrazole-pyridine conjugates 9F and 10F having amide tethers.
Scheme 9: A tentative mechanism for the formation of pyrazole conjugates with thioamide and amide linkage.
Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects
- Shivani Gulati,
- Stephy Elza John and
- Nagula Shankaraiah
Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71
- atorvastatin, a potent HMG-CoA reductase inhibitor. Dömling and co-workers efficiently demonstrated an Ugi-based MCR approach towards the synthesis of atorvastatin in four steps ruling out the lengthy seven step protocol, and paving a rapid entry to the drug discovery market [12]. Alternatively, microwave
- found to be abundant in a plethora of lead molecules and marketed drugs like atorvastatin (57), elopiprazole (58), isamoltane (59) and tolmetin (60, Figure 5) [59][60]. The diverse pharmacological activities of pyrroles enlivened Kumar and co-workers [61] to report a facile and eco-friendly microwave
Graphical Abstract
Figure 1: Marketed drugs with acridine moiety.
Scheme 1: Synthesis of 4-arylacridinediones.
Scheme 2: Proposed mechanism for acridinedione synthesis.
Scheme 3: Synthesis of tetrahydrodibenzoacridinones.
Scheme 4: Synthesis of naphthoacridines.
Scheme 5: Plausible mechanism for naphthoacridines.
Figure 2: Benzoazepines based potent molecules.
Scheme 6: Synthesis of azepinone.
Scheme 7: Proposed mechanism for azepinone formation.
Scheme 8: Synthesis of benzoazulenen-1-one derivatives.
Scheme 9: Proposed mechanism for benzoazulene-1-one synthesis.
Figure 3: Indole-containing pharmacologically active molecules.
Scheme 10: Synthesis of functionalized indoles.
Scheme 11: Plausible mechanism for the synthesis of functionalized indoles.
Scheme 12: Synthesis of spirooxindoles.
Scheme 13: Synthesis of substituted spirooxindoles.
Scheme 14: Plausible mechanism for the synthesis of substituted spirooxindoles.
Scheme 15: Synthesis of pyrrolidinyl spirooxindoles.
Scheme 16: Proposed mechanism for pyrrolidinyl spirooxindoles.
Figure 4: Pyran-containing biologically active molecules.
Scheme 17: Synthesis of functionalized benzopyrans.
Scheme 18: Plausible mechanism for synthesis of benzopyran.
Scheme 19: Synthesis of indoline-spiro-fused pyran derivatives.
Scheme 20: Proposed mechanism for indoline-spiro-fused pyran.
Scheme 21: Synthesis of substituted naphthopyrans.
Figure 5: Marketed drugs with pyrrole ring.
Scheme 22: Synthesis of tetra-substituted pyrroles.
Scheme 23: Mechanism for silica-supported PPA-SiO2-catalyzed pyrrole synthesis.
Scheme 24: Synthesis of pyrrolo[1,10]-phenanthrolines.
Scheme 25: Proposed mechanism for pyrrolo[1,10]-phenanthrolines.
Figure 6: Marketed drugs and molecules containing pyrimidine and pyrimidinones skeletons.
Scheme 26: MWA-MCR pyrimidinone synthesis.
Scheme 27: Two proposed mechanisms for pyrimidinone synthesis.
Scheme 28: MWA multicomponent synthesis of dihydropyrimidinones.
Scheme 29: Proposed mechanism for dihydropyrimidinones.
Figure 7: Biologically active fused pyrimidines.
Scheme 30: MWA- MCR for the synthesis of pyrrolo[2,3-d]pyrimidines.
Scheme 31: Proposed mechanism for pyrrolo[2,3-d]pyrimidines.
Scheme 32: Synthesis of substituted pyrrolo[2,3-d]pyrimidine-2,4-diones.
Scheme 33: Probable pathway for pyrrolo[2,3-d]pyrimidine-2,4-diones.
Scheme 34: Synthesis of pyridopyrimidines.
Scheme 35: Plausible mechanism for the synthesis of pyridopyrimidines.
Scheme 36: Synthesis of dihydropyridopyrimidine and dihydropyrazolopyridine.
Scheme 37: Proposed mechanism for the formation of dihydropyridopyrimidine.
Scheme 38: Synthesis of thiopyrano[4,3-d]pyrimidines.
Scheme 39: Plausible mechanism for the synthesis of thiopyrano[4,3-d]pyrimidines.
Scheme 40: Synthesis of decorated imidazopyrimidines.
Scheme 41: Proposed mechanism for imidazopyrimidine synthesis.
Figure 8: Pharmacologically active molecules containing purine bases.
Scheme 42: Synthesis of aza-adenines.
Scheme 43: Synthesis of 5-aza-7-deazapurines.
Scheme 44: Proposed mechanism for deazapurines synthesis.
Figure 9: Biologically active molecules containing pyridine moiety.
Scheme 45: Synthesis of steroidal pyridines.
Scheme 46: Proposed mechanism for steroidal pyridine.
Scheme 47: Synthesis of N-alkylated 2-pyridones.
Scheme 48: Two possible mechanisms for pyridone synthesis.
Scheme 49: Synthesis of pyridone derivatives.
Scheme 50: Postulated mechanism for synthesis of pyridone.
Figure 10: Biologically active fused pyridines.
Scheme 51: Benzimidazole-imidazo[1,2-a]pyridines synthesis.
Scheme 52: Mechanism for the synthesis of benzimidazole-imidazo[1,2-a]pyridines.
Scheme 53: Synthesis of pyrazolo[3,4-b]pyridine-5-spirocycloalkanedione derivatives.
Scheme 54: Proposed mechanism for spiro-pyridines.
Scheme 55: Functionalized macrocyclane-fused pyrazolo[3,4-b]pyridine derivatives.
Scheme 56: Mechanism postulated for macrocyclane-fused pyrazolo[3,4-b]pyridine.
Scheme 57: Generation of pyrazolo[3,4-b]pyridines.
Scheme 58: Proposed mechanism for the synthesis of pyrazolo[3,4-b]pyridines.
Scheme 59: Proposed mechanism for the synthesis of azepinoindole.
Figure 11: Pharmaceutically important molecules with quinoline moiety.
Scheme 60: Povarov-mediated quinoline synthesis.
Scheme 61: Proposed mechanism for Povarov reaction.
Scheme 62: Synthesis of pyrazoloquinoline.
Scheme 63: Plausible mechanism for pyrazoloquinoline synthesis.
Figure 12: Quinazolinones as pharmacologically significant scaffolds.
Scheme 64: Four-component reaction for dihydroquinazolinone.
Scheme 65: Proposed mechanism for dihydroquinazolinones.
Scheme 66: Synthesis purine quinazolinone and PI3K-δ inhibitor.
Scheme 67: Synthesis of fused benzothiazolo/benzoimidazoloquinazolinones.
Scheme 68: Proposed mechanism for fused benzothiazolo/benzoimidazoloquinazolinones.
Scheme 69: On-water reaction for synthesis of thiazoloquinazolinone.
Scheme 70: Proposed mechanism for the thiazoloquinazolinone synthesis.
Scheme 71: β-Cyclodextrin-mediated synthesis of indoloquinazolinediones.
Scheme 72: Proposed mechanism for synthesis of indoloquinazolinediones.
Figure 13: Triazoles-containing marketted drugs and pharmacologically active molecules.
Scheme 73: Cu(I) DAPTA-catalyzed 1,2,3-triazole formation.
Scheme 74: Mechanism for Cu(I) DAPTA-catalyzed triazole formation.
Scheme 75: Synthesis of β-hydroxy-1,2,3-triazole.
Scheme 76: Proposed mechanism for synthesis of β-hydroxy-1,2,3-triazoles.
Scheme 77: Synthesis of bis-1,2,4-triazoles.
Scheme 78: Proposed mechanism for bis-1,2,4-triazoles synthesis.
Figure 14: Thiazole containing drugs.
Scheme 79: Synthesis of a substituted thiazole ring.
Scheme 80: Synthesis of pyrazolothiazoles.
Figure 15: Chromene containing drugs.
Scheme 81: Magnetic nanocatalyst-mediated aminochromene synthesis.
Scheme 82: Proposed mechanism for the synthesis of chromenes.
Synthesis of dibenzosuberenone-based novel polycyclic π-conjugated dihydropyridazines, pyridazines and pyrroles
- Ramazan Koçak and
- Arif Daştan
Beilstein J. Org. Chem. 2021, 17, 719–729, doi:10.3762/bjoc.17.61
- ingredient of many top-selling drugs such as atorvastatin, sunitinib, and ketorolac, contains a pyrrole unit (Figure 1) [49]. Due to these unique features, the synthesis of new dihydropyridazines, pyridazines, and pyrroles, which have the potential to be used in many applications, is very important. inverse
Graphical Abstract
Figure 1: Structures of dibenzosuberenone 1 and pyridazine and pyrrole derivatives.
Figure 2: Structures of s-tetrazines 2a–l.
Scheme 1: Inverse electron-demand Diels–Alder reactions of dibenzosuberenone (1) with tetrazines 2a–l.
Scheme 2: Inverse electron-demand Diels–Alder reactions between dibenzosuberenone 1 and tetrazines 2ka and 2lb...
Scheme 3: Proposed reaction mechanism for the formation of dibenzosuberenone derivatives 3 and 4.
Scheme 4: Proposed mechanism for the formation of 5l.
Scheme 5: Oxidation of dihydropyridazines 3a–f. All reactions were carried in CH2Cl2 at room temperature (4e:...
Scheme 6: Synthesis of pyrrole 10a. a1.34 mmol 4a, Zinc (for 10aa: 6.68 mmol, for 10ab: 13.36 mmol), 10 mL gl...
Scheme 7: Synthesis of pyrrole 10b. a1.21 mmol 4b, 12.10 mmol Zinc, 118 °C, 2 h. b1.13 mmol 10ba, 1.69 mmol K...
Scheme 8: Synthesis of p-quinone methides 13–16. a1.77 mmol 11, 1.77 mmol 2, 5 mL toluene, 80 °C (13a: overni...
Scheme 9: Proposed mechanism for the formation of 13.
Figure 3: UV–vis spectra of 3c–f and 3k in CH3CN at rt (c = 5 μM).
Figure 4: Fluorescence spectra of 3c–f and 3k in CH3CN at rt (c = 5 μM).
Figure 5: Ambient (top) and fluorescence (bottom, under 365 nm UV light) images of 3c–f and 3k in CH3CN.
Characterization of two new degradation products of atorvastatin calcium formed upon treatment with strong acids
- Jürgen Krauß,
- Monika Klimt,
- Markus Luber,
- Peter Mayer and
- Franz Bracher
Beilstein J. Org. Chem. 2019, 15, 2085–2091, doi:10.3762/bjoc.15.206
- , Germany 10.3762/bjoc.15.206 Abstract Atorvastatin calcium (Lipitor®, Sortis®) is a well-established cholesterol synthesis enzyme (CSE) inhibitor commonly used in the therapy of hypercholesterolemia. This drug is known to be sensitive to acid treatment, but only little data has been published on the
- structures of the degradation products. Here we report the identification of two novel degradation products of atorvastatin, which are formed only under drastic acidic conditions. While treatment with conc. sulfuric acid led to a loss of the carboxanilide residue (accompanied by an expectable lactonization
- NMR spectroscopy, HRMS data and X-ray crystal structure analysis. Keywords: atorvastatin; crystal structure; cyclization; degradation products; fragmentation; stress test; Introduction Over the past decades, the general trend toward globalization of the supply chains for active pharmaceutical
Graphical Abstract
Figure 1: Atorvastatin calcium trihydrate (1) and previously published decomposition products arising from tr...
Scheme 1: Formation of novel artefacts 6 and 7 under extremely strong acidic conditions.
Figure 2: Top: Molecular structure of artefact 6. Shown here is the molecular structure of one of three indep...
Figure 3: Separation of atorvastatin (1; retention time: 5.8 min) from the four decomposition products 2 (ret...
Scheme 2: Proposed mechanism for the formation of desamidated product 7.
Scheme 3: Proposed mechanism for the formation of bridged product 6 under cyclization, isopropyl migration an...
Application of chiral 2-isoxazoline for the synthesis of syn-1,3-diol analogs
- Juanjuan Feng,
- Tianyu Li,
- Jiaxin Zhang and
- Peng Jiao
Beilstein J. Org. Chem. 2019, 15, 1840–1847, doi:10.3762/bjoc.15.179
- well tolerate PTSA-catalyzed methanolysis. Conclusion In conclusion, we synthesized tert-butyl (3S,5R)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate (16), which is enantiomeric to a key intermediate for atorvastatin, from a chiral 2-isoxazoline (3). The β-hydroxy ketone 7 obtained from 3 could
Graphical Abstract
Scheme 1: Accesses to tert-butyl 3,5-O-isopropylidene-3,5-dihydroxyhexanoates. (a) Previous methods using Cla...
Scheme 2: Attempted oxidations of 4.
Scheme 3: Preparations of 16 and related syn-1,3-diol compounds.
Scheme 4: Attempted oxidations of 6'.
Scheme 5: Attempted selective protections of internal 1,3-hydroxy groups: (a) acetonizations of 1,3-diols; (b...
An efficient and facile access to highly functionalized pyrrole derivatives
- Meng Gao,
- Wenting Zhao,
- Hongyi Zhao,
- Ziyun Lin,
- Dongfeng Zhang and
- Haihong Huang
Beilstein J. Org. Chem. 2018, 14, 884–890, doi:10.3762/bjoc.14.75
- in medicinal chemistry (Figure 1), such as analgesic agent 1 [1], BET bromodomain inhibitor 2 [2], selective PARP-1 inhibitor 3 [3], histone deacetylase inhibitor with antitumor activity 4 [4], Flavivirus inhibitor 5 [5], and for treating cardiovascular diseases (atorvastatin, 6) [6]. A number of
Graphical Abstract
Figure 1: Representative pyrrolo[3,4-c]pyrrole-1,3-diones and polysubstituted pyrrole derivatives.
Scheme 1: Synthetic pathway for the preparation of pyrrolo[3,4-c]pyrrole-1,3-diones and highly substituted py...
Scheme 2: Scope of one-pot synthesis of pyrrolo[3,4-c]pyrrole-1,3-diones 12a–k. General reaction conditions: ...
Scheme 3: Scope of the synthesis of highly substituted pyrrole derivatives 13a–n. General reaction conditions...
Scheme 4: Synthesis of 13k from 12d and ethylamine.
Efficient synthesis of π-conjugated molecules incorporating fluorinated phenylene units through palladium-catalyzed iterative C(sp2)–H bond arylations
- Fatiha Abdelmalek,
- Fazia Derridj,
- Safia Djebbar,
- Jean-François Soulé and
- Henri Doucet
Beilstein J. Org. Chem. 2015, 11, 2012–2020, doi:10.3762/bjoc.11.218
- ]. In addition, several fluorinated heterobiaryls such as atorvastatin, rosuvastatin, or pitavastatin have been developed as drugs and commercialized by pharmaceutical companies [5]. In both areas, fluorine atoms can modify the properties of organic compounds. It is established that fluorine atoms
Graphical Abstract
Figure 1: Different pathways for the synthesis of π-conjugated molecules incorporating fluorinated phenylene ...
Scheme 1: Pd-catalyzed desulfitative direct arylations of heteroarenes using 2,3,4-trifluorobenzenesulfonyl c...
Scheme 2: Pd-catalyzed second arylation of 1 and 2. i) PdCl(C3H5)(dppb) (2 mol %), KOAc (2 equiv), DMA, 150 °...
Scheme 3: Pd-catalyzed direct regioselective arylation of 1-methyl-2-(2,3,4-trifluorophenyl)pyrrole (4). i) P...
Scheme 4: Pd-catalyzed direct regioselective arylation of 3-(2,3,4-trifluorophenyl)thiophenes. i) PdCl(C3H5)(...
Scheme 5: Pd-catalyzed desulfitative direct arylations of heteroarenes using difluorobenzenesulfonyl chloride...
Scheme 6: Pd-catalyzed second direct regioselective arylation of difluorophenylheteroarenes 19-23. i) PdCl(C3H...
Scheme 7: Pd-catalyzed iterative direct arylations of heteroarenes–fluorobenzene triads and tetrad. i) PdCl2(...
Scheme 8: Reactivity of pentafluorobenzenesulfonyl chloride in Pd-catalyzed direct desulfitative arylation of...
Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams
- Katherine M. Byrd
Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60
Graphical Abstract
Scheme 1: Generic mechanism for the conjugate addition reaction.
Figure 1: Methods to activate unsaturated amide/lactam systems.
Scheme 2: DCA of Grignard reagents to an L-ephedrine derived chiral α,β–unsaturated amide.
Figure 2: Chiral auxiliaries used in DCA reactions.
Scheme 3: Comparison between auxiliary 5 and the Oppolzer auxiliary in a DCA reaction.
Scheme 4: Use of Evans auxiliary in a DCA reaction.
Figure 3: Lewis acid complex of the Evans auxiliary [43].
Scheme 5: DCA reactions of α,β-unsaturated amides utilizing (S,S)-(+)-pseudoephedrine and the OTBS-derivative...
Figure 4: Proposed model accounting for the diastereoselectivity observed in the 1,4-addition of Bn2NLi to α,...
Scheme 6: An example of a tandem conjugate addition–α-alkylation reaction of an α,β-unsaturated amide utilizi...
Scheme 7: Conjugate addition to an α,β-unsaturated bicyclic lactam leading to (+)-paroxetine and (+)-femoxeti...
Scheme 8: Intramolecular conjugate addition reaction to α,β-unsaturated amide.
Scheme 9: Conjugate addition to an α,β-unsaturated pyroglutamate derivative.
Scheme 10: Cu(I)–NHC-catalyzed asymmetric silylation of α,β-unsaturated lactams and amides.
Scheme 11: Asymmetric copper-catalyzed 1,4-borylation of an α,β-unsaturated amide.
Scheme 12: Asymmetric cross-coupling 49 to phenyl chloride.
Scheme 13: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam.
Scheme 14: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide.
Scheme 15: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide using a chiral bicyclic dien...
Scheme 16: Synthesis of (R)-(−)-baclofen through a rhodium-catalyzed asymmetric 1,4-arylation of lactam 58.
Scheme 17: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide and lactam employing organo[...
Scheme 18: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam employing benzofuran-2-ylzi...
Figure 5: Further chiral ligands that have been used in rhodium-catalyzed 1,4-additions of α,β-unsaturated am...
Scheme 19: Palladium-catalyzed asymmetric 1,4-arylation of arylsiloxanes to a α,β-unsaturated lactam.
Scheme 20: SmI2-mediated cyclization of α,β-unsaturated Weinreb amides.
Figure 6: Chiral Lewis acid complexes used in the Mukaiyama–Michael addition of α,β-unsaturated amides.
Scheme 21: Mukaiyama–Michael addition of thioester silylketene acetal to α,β-unsaturated N-alkenoyloxazolidino...
Scheme 22: Asymmetric 1,4-addition of aryl acetylides to α,β-unsaturated thioamides.
Scheme 23: Asymmetric 1,4-addition of alkyl acetylides to α,β-unsaturated thioamides.
Scheme 24: Asymmetric vinylogous conjugate additions of unsaturated butyrolactones to α,β-unsaturated thioamid...
Scheme 25: Gd-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrroles [205].
Scheme 26: Lewis acid-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrazole 107.
Scheme 27: Lewis acid mediated 1,4-addition of dibenzyl malonate to α,β-unsaturated N-acylpyrroles.
Scheme 28: Chiral Lewis acid mediated 1,4-radical addition to α,β-unsaturated N-acyloxazolidinone [224].
Scheme 29: Aza-Michael addition of O-benzylhydroxylamine to an α,β-unsaturated N-acylpyrazole.
Scheme 30: An example of the aza-Michael addition of secondary aryl amines to an α,β-unsaturated N-acyloxazoli...
Scheme 31: Aza-Michael additions of anilines to a α,β-unsaturated N-alkenoyloxazolidinone catalyzed by palladi...
Scheme 32: Aza-Michael additions of aniline to an α,β-unsaturated N-alkenoylbenzamide and N-alkenoylcarbamate ...
Scheme 33: Difference between aza-Michael addition ran using the standard protocol versus the slow addition pr...
Scheme 34: Aza-Michael additions of aryl amines salts to an α,β-unsaturated N-alkenoyloxazolidinone catalyzed ...
Scheme 35: Aza-Michael addition of N-alkenoyloxazolidiniones catalyzed by samarium diiodide [244].
Scheme 36: Asymmetric aza-Michael addition of p-anisidine to α,β-unsaturated N-alkenoyloxazolidinones catalyze...
Scheme 37: Asymmetric aza-Michael addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones catalyzed by i...
Scheme 38: Asymmetric 1,4-addition of purine to an α,β-unsaturated N-alkenoylbenzamide catalyzed by (S,S)-(sal...
Scheme 39: Asymmetric 1,4-addition of phosphites to α,β-unsaturated N-acylpyrroles.
Scheme 40: Asymmetric 1,4-addition of phosphine oxides to α,β-unsaturated N-acylpyrroles.
Scheme 41: Tandem Michael-aldol reaction catalyzed by a hydrogen-bonding organocatalyst.
Scheme 42: Examples of the sulfa-Michael–aldol reaction employing α,β-unsaturated N-acylpyrazoles.
Scheme 43: Example of the sulfa-Michael addition of α,β-unsaturated N-alkenoyloxazolidinones.
Figure 7: Structure of cinchona alkaloid-based squaramide catalyst.
Scheme 44: Asymmetric intramolecular oxa-Michael addition of an α,β-unsaturated amide.
Scheme 45: Formal synthesis atorvastatin.
N-Heterocyclic carbene–palladium catalysts for the direct arylation of pyrrole derivatives with aryl chlorides
- Ismail Özdemir,
- Nevin Gürbüz,
- Nazan Kaloğlu,
- Öznur Doğan,
- Murat Kaloğlu,
- Christian Bruneau and
- Henri Doucet
Beilstein J. Org. Chem. 2013, 9, 303–312, doi:10.3762/bjoc.9.35
- important research area in organic synthesis as such motives are known to be present in several bioactive molecules, such as Atorvastatin, which is used for lowering blood cholesterol, Fendosal, which is an anti-inflammatory agent, or Tanaproget, which is a progesterone-receptor agonist (Figure 1). The
Graphical Abstract
Figure 1: Examples of pyrrole-containing bioactive compounds.
Scheme 1: Synthesis of Pd–NHC complexes.
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
- core structure of atorvastatin (1, Lipitor; Figure 1), the best-selling drug substance of the last few years, does contain a penta-substituted pyrrole ring. This drug is an example of a competitive HMG-CoA-reductase inhibitor belonging to the 7-substituted 3,5-dihydroxyheptanoic acid family. In
- atorvastatin this important syn-1,3-diol moiety is connected to the other functional constituents through a fully substituted pyrrole ring instead of the more elaborate systems which are encountered in other members of this family. The initial synthesis of atorvastatin was reported by the Warner–Lambert
- atorvastatin which has a five times greater potency then the initial lead, the fungal metabolite compactin (5, Figure 2). Although it was possible to construct such fully substituted pyrrole rings by ZnCl2-catalysed condensation reactions between a functionalised enamine 6 and simple benzoin (7), this method
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).
