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Search for "drug substance" in Full Text gives 7 result(s) in Beilstein Journal of Organic Chemistry.
New synthesis of a late-stage tetracyclic key intermediate of lumateperone
- Mátyás Milen,
- Bálint Nyulasi,
- Tamás Nagy,
- Gyula Simig and
- Balázs Volk
Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66
- Matyas Milen Balint Nyulasi Tamas Nagy Gyula Simig Balazs Volk Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, 1475 Budapest, P.O. Box 100, Hungary 10.3762/bjoc.18.66 Abstract New approaches have been tested for the synthesis of lumateperone intermediates. As a result of
- a Fischer indole synthesis. The inexpensive starting material, the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability. Keywords: drug substance; indole synthesis; key intermediate; protecting group; telescoping
Graphical Abstract
Figure 1: Structure of lumateperone.
Scheme 1: First synthetic route leading to lumateperone (1).
Scheme 2: Alternate synthesis of lumateperone.
Scheme 3: Alternate synthetic approaches leading to racemic lumateperone ((±)-1)).
Scheme 4: Planned new synthesis of key intermediate (±)-9a.
Scheme 5: New synthesis of key intermediate (±)-9a.
Scheme 6: Trifluoroacetylation of tetrahydroquinoxaline (37).
Rearrangement of o-(pivaloylaminomethyl)benzaldehydes: an experimental and computational study
- Csilla Hargitai,
- Györgyi Koványi-Lax,
- Tamás Nagy,
- Péter Ábrányi-Balogh,
- András Dancsó,
- Gábor Tóth,
- Judit Halász,
- Angéla Pandur,
- Gyula Simig and
- Balázs Volk
Beilstein J. Org. Chem. 2020, 16, 1636–1648, doi:10.3762/bjoc.16.136
- Csilla Hargitai Gyorgyi Kovanyi-Lax Tamas Nagy Peter Abranyi-Balogh Andras Dancso Gabor Toth Judit Halasz Angela Pandur Gyula Simig Balazs Volk Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, H-1475 Budapest, Hungary Medicinal Chemistry Research Group, Research
Graphical Abstract
Scheme 1: Rearrangement of methylenedioxy-substituted aminoaldehyde 1a to regioisomer 2a and formation of the...
Scheme 2: Synthesis of 1-arylisoindoles 6 and formation of dimers 5.
Scheme 3: Rearrangement of aminoaldehydes 1 to regioisomers 2 and formation of dimer-like products 3 and 8.
Figure 1: X-ray structures of compounds 3b (left) and 8b (right).
Scheme 4: Proposed mechanism of the isomerization of aldehydes 1 via isoindoles 4.
Scheme 5: Proposed mechanism of the formation of dimer-like products 3a,b.
Scheme 6: Proposed mechanism for the formation of dimer-like products 8a,b.
Scheme 7: Dimerization of indole under acidic conditions.
Figure 2: Gibbs free energy diagram for the 1→2 rearrangement.
Scheme 8: Reaction of o-(pivaloylaminomethyl)benzaldehyde (1e) to give dimer-like products 23a and 23b.
Figure 3: X-ray structures of compounds 23a (left) and 23b (right).
Figure 4: Structures of the minimal energy conformer of stereoisomer 23a and those of two minimal energy conf...
Photo, thermal and chemical degradation of riboflavin
- Muhammad Ali Sheraz,
- Sadia Hafeez Kazi,
- Sofia Ahmed,
- Zubair Anwar and
- Iqbal Ahmad
Beilstein J. Org. Chem. 2014, 10, 1999–2012, doi:10.3762/bjoc.10.208
- change was observed whereas color continued to change in the synthetic samples and become more discolored upon continuous irradiation. An increase in color change in both powders was noted when the drug substance was compressed with an IR press at high pressure prior to exposure [73]. In the case of
Graphical Abstract
Figure 1: Structures of RF and its photoproducts.
Figure 2: A general scheme for the photodegradation of RF in aqueous solution.
Figure 3: log k–pH profiles for the photolysis of RF in aqueous solution using UV light (∆) and visible light...
Figure 4: log k–pH profiles for the photolysis of FMF (10−4 M) in alkaline solution under aerobic (○) and ana...
Figure 5: k'–pH profiles for the photolysis of FMF (10−4 M) in acidic solution under aerobic (○) and anaerobi...
Figure 6: Plots of k` versus pH for phosphate (▲) and sulfate (●) anion-catalyzed photodegradation of RF (5 ×...
Figure 7: log kobs–pH profiles for the photolysis of RF (5 × 10−5 M) in 0.1–0.5 M borate buffer. Experimental...
Figure 8: log kobs–pH profiles for the photolysis of RF (5 × 10−5 M) in 0.2–1.0 M citrate buffer. Experimenta...
Figure 9: k'–pH profile for the photolysis of RF (5 × 10−5 M) in the presence of CF (0.5–2.5 × 10−4 M). Exper...
An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles
- Marcus Baumann and
- Ian R. Baxendale
Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265
Graphical Abstract
Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
Scheme 3: Synthesis of 3-picoline and nicotinic acid.
Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
Scheme 8: Synthesis of rosiglitazone.
Scheme 9: Syntheses of 2-pyridones.
Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
Scheme 11: Polymer-assisted synthesis of rosiglitazone.
Scheme 12: Synthesis of pioglitazone.
Scheme 13: Meerwein arylation reaction towards pioglitazone.
Scheme 14: Route towards pioglitazone utilising tyrosine.
Scheme 15: Route towards pioglitazone via Darzens ester formation.
Scheme 16: Syntheses of the thiazolidinedione moiety.
Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
Scheme 19: Synthesis of moxifloxacin.
Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
Scheme 21: Synthesis of levofloxacin.
Scheme 22: Alternative approach to the levofloxacin core 1.125.
Figure 3: Structures of nifedipine, amlodipine and clevidipine.
Scheme 23: Mg3N2-mediated synthesis of nifedipine.
Scheme 24: Synthesis of rac-amlodipine as besylate salt.
Scheme 25: Aza Diels–Alder approach towards amlodipine.
Scheme 26: Routes towards clevidipine.
Figure 4: Examples of piperidine containing drugs.
Figure 5: Discovery of tiagabine based on early leads.
Scheme 27: Synthetic sequences to tiagabine.
Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
Scheme 28: Enantioselective synthesis of solifenacin.
Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
Scheme 30: Improved route to carmegliptin.
Figure 9: Structures of lamivudine and zidovudine.
Scheme 31: Typical routes accessing uracil, thymine and cytosine.
Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
Scheme 33: Synthesis of lamivudine.
Scheme 34: Synthesis of raltegravir.
Scheme 35: Mechanistic studies on the formation of 3.22.
Figure 10: Structures of selected pyrimidine containing drugs.
Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
Scheme 37: Synthesis of imatinib.
Scheme 38: Flow synthesis of imatinib.
Scheme 39: Syntheses of erlotinib.
Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
Scheme 41: Synthesis of lapatinib.
Scheme 42: Synthesis of rosuvastatin.
Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
Scheme 44: Syntheses of varenicline and its key building block 4.5.
Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
Scheme 46: Asymmetric synthesis of bortezomib.
Figure 13: Structures of some prominent piperazine containing drugs.
Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
Scheme 48: Syntheses of azelastine (5.1).
Figure 15: Structures of captopril, enalapril and cilazapril.
Scheme 49: Synthesis of cilazapril.
Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
Scheme 50: Synthesis of lamotrigine.
Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
Scheme 52: Conventional synthesis of imiquimod (no yields reported).
Scheme 53: Synthesis of imiquimod.
Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
Figure 18: Structures of various anti HIV-medications.
Scheme 55: Synthesis of abacavir.
Figure 19: Structures of diazepam compared to modern replacements.
Scheme 56: Synthesis of ocinaplon.
Scheme 57: Access to zaleplon and indiplon.
Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
Scheme 60: Early synthetic route to sildenafil.
Scheme 61: Convergent preparations of sildenafil.
Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
Scheme 62: Short route to imidazotriazinones.
Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
Scheme 64: Bayer’s approach to the vardenafil core.
Scheme 65: Large scale synthesis of vardenafil.
Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
Scheme 67: Different routes to temozolomide.
Scheme 68: Safer route towards temozolomide.
Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide
- Suri Babu Madasu,
- Nagaji Ambabhai Vekariya,
- M. N. V. D. Hari Kiran,
- Badarinadh Gupta,
- Aminul Islam,
- Paul S. Douglas and
- Korupolu Raghu Babu
Beilstein J. Org. Chem. 2012, 8, 1400–1405, doi:10.3762/bjoc.8.162
- drug substance should be not more than 0.15% and 0.10%, respectively [11], depending on the maximum daily dose. To meet the meticulous regulatory requirements, the impurities present in the drug substance must be identified and characterized. By knowing the chemical structure of these impurities
Graphical Abstract
Figure 1: Related compounds of eletriptan hydrobromide.
Scheme 1: Synthetic route of eletriptan hydrobromide. Reagents and conditions: (i) Acetic anhydride, TEA, DMF...
Scheme 2: Dimerization of 13. Reagents and conditions: (i) NaH, THF, 30–35 °C, 2 h; 11.6% yield after column ...
Scheme 3: Formation of the isomers 3 and 4. Reagents and conditions: (i) Aqueous hydrogen peroxide, methanol,...
Scheme 4: Synthesis of impurity 5. Reagents and conditions: (i) Acetic anhydride, TEA, DMF, 90–100 °C; (ii) p...
Scheme 5: Debromination of 9 to 6. Reagents and conditions: Palladium on carbon, ethanol, ca. 7 bar, 25–30 °C...
Scheme 6: Formation of 7. Reagents, conditions: (i) (a) K2CO3, methanol, reflux, 2 days; 40% yield after colu...
Scheme 7: Synthesis of the tetracyclic compound 7. Reagents and conditions: (i) aqueous hydrogen peroxide, wa...
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
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
- . Keywords: impurity profile; related substances; sertindole; Introduction The safety of a drug product is not only dependent on the toxicological properties of the active drug substance (or API), but also on the impurities formed during the various chemical transformations. Therefore, identification
- , quantification, and control of impurities in the drug substance and drug product are important parts of drug development for obtaining marketing approval. It is more challenging for an organic chemist to identify the impurities which are formed in very small quantities in a drug substance. Since most of the time
- difficult for the organic chemist who must then design a synthesis, which is time consuming. The development of a drug substance is incomplete without the identification of an impurity profile involved in the process. Furthermore, it is not mandatory to design synthetic routes for the impurities. Thus, in
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%).
