A5052019659- Crystallization and Solubility Studies
- Synthesis and Biological Evaluation
- X-ray Diffraction in Crystallography
- Organic Chemistry Cycloaddition Reactions
- Synthesis of Organic Compounds
- Carcinogens and Genotoxicity Assessment
- Chemical Synthesis and Reactions
- Synthesis of heterocyclic compounds
- Synthetic Organic Chemistry Methods
- Water Treatment and Disinfection
- Oxidative Organic Chemistry Reactions
- Bioactive Compounds and Antitumor Agents
- Analytical Chemistry and Chromatography
- Radical Photochemical Reactions
- Coordination Chemistry and Organometallics
- Synthesis and Catalytic Reactions
- Computational Drug Discovery Methods
- Asymmetric Synthesis and Catalysis
- Traditional and Medicinal Uses of Annonaceae
- Pesticide and Herbicide Environmental Studies
- Carbohydrate Chemistry and Synthesis
- Cardiac electrophysiology and arrhythmias
- Synthesis and Reactions of Organic Compounds
- Ubiquitin and proteasome pathways
- Synthesis of Tetrazole Derivatives
GlaxoSmithKline (Netherlands)
2025
GlaxoSmithKline (United Kingdom)
2002-2024
Age UK
2023
North Hertfordshire College
2019
University of Hertfordshire
2012
Cytokinetics (United States)
2010
University of East Anglia
1997-2002
University of Bristol
2002
University of Central Lancashire
1997-1998
The presence of low levels N-nitroso-N,N-dimethylamine (NDMA) in ranitidine hydrochloride drug products has been reported by regulatory agencies. GlaxoSmithKline undertook a root cause analysis to investigate this observation using contemporaneous, highly sensitive analytical methodologies. suggested that the NDMA results from slow degradation molecule. Analysis suitably isotopically labeled confirmed formation solely an intermolecular reaction without involvement impurities. Factors...
The discovery and development of an efficient more sustainable manufacturing route to the anti-pneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. existing commercial delivers a poor yield product uses expensive reagents. new synthesis commences with readily available phthalic anhydride, which converted 1,4-isochromandione 5 then by reaction 4-(4-chlorophenyl)cyclohexanecarboxylic acid 3 using key bromination, Rosenmund...
The ICH M7 guidance provides a series of flexible control options for the (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes option 4, which leverages existing process knowledge and/or data to justify PMIs without need routine analytical release testing during manufacturing. One such technique highlighted uses systematic, semiquantitative calculations define degree "purge" within synthetic route an active pharmaceutical ingredient (API)...
The increased usage of purge arguments for demonstrating control mutagenic impurities in drug substances, accordance with ICH M7, necessitates an increasingly standardized approach to their implementation across industry. strength the is highly reliant upon a conservative principles maintain regulatory confidence. Different parameters may influence calculation, such as reactivity, solubility, and volatility. While reactivity data are commonly available literature, there comparatively fewer...
An efficient two step procedure for the synthesis of 2,3,4,9-tetrahydro-1H-xanthene-1,9-diones is described. A study their conjugate additions has shown them to be Michael acceptors. Reaction 2,3,4,9-tetrahydro-1H-xanthene-1,9-dione with tris(methylthio)methyllithium, followed by mercury(II) catalysed methanolysis, gave methyl 1-hydroxy-9-oxo-3,4,4a,9-tetrahydro-2H-xanthene-4a-carboxylate, nucleus secalonic acids and other natural products
ICH M7 provides several risk-based control options to manage mutagenic and potentially impurities (MI PMIs) in the manufacture of pharmaceuticals. A Working Group International Consortium for Innovation Quality Pharmaceutical Development (IQ, www.iqconsortium.org) performed a survey pharmaceutical manufacturers gain insight into use regulatory acceptance impurity strategies across industry. Information on was collected late-stage clinical commercial programs with feedback from FDA, EMA,...
[reaction: see text]. Irradiation of benzotriazole with a variety maleimide derivatives leads to the stereo- and regioselective formation aryl [2 + 2] photocycloaddition products. Further studies 2-alkyl indicates that in case parent this cycloaddition proceeds selectively via 2H-tautomer.
The discovery and development of an efficient manufacturing route to the SSRI-5-HT1A receptor antagonist 6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one (SB-649915) 1 is described. existing involved coupling quinoline 6 with piperidine 5 was considered lengthy as a consequence nine synthetic steps required prepare 5. Two new routes key intermediate are identified which deliver this compound in five two respectively, from readily available...
A synthesis of the pleuromutilin antibiotic SB-268091 is described which includes a new and improved route to quinuclidine-4-thiol ligand. This chemistry has been run on multikilo scale involved reductive double debenzylation using sodium in liquid ammonia. Alternative conditions have developed prepare avoid use The generality this process differentially S-protected quinuclidine-4-thiols also discussed exemplified by preparation range analogues.
The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}−4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. existing GSK923295A was expensive, nonrobust, used nonideal reagents, consistently struggled deliver API needed for clinical studies. new synthesis commences from readily available l-phenylalaninol, which smoothly...
The addition of sulfenes to substituted enaminoketones, followed by a facile Cope elimination, provides efficient access diverse series 1,2-oxathiine 2,2-dioxides.
The development of the synthetic process to PPAR-α receptor antagonist 5-((4-(tert-butoxy)-3-methylphenoxy)methyl)-3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazole (GW641597X) 1 is described. discussion ranges from initial supply route, used deliver early batches for preliminary safety studies enable dosing in man, an efficient manufacturing which delivered 35 kg drug substance following on a pilot plant campaign. includes key oxidative Baeyer–Villiger reaction, where identified sodium perborate...
The acid catalysed rearrangement of 1-hydroxy-2,3,4,4a-tetrahydro-9H-xanthen-9-ones can give 1-alkoxy- or 1-alkylidene-1,2,3,4-tetrahydro-9H-xanthen-9-ones and/or 3,4-dihydro-9H-xanthen-9-ones depending on the conditions employed. last compounds undergo facile Diels–Alder cycloaddition reactions.
The multigram synthesis of (2S)- and (2R)-2-(1-methylethyl)-5-oxo-2-phenylpentanenitriles 9a 9b is described, using either (4R)-2,2-dimethyl-1,3-dioxolan-4-ylmethanol or (2R)-butane-1,2,4-triol as chiral auxiliary. configuration an intermediate dioxolane 10b assigned by X-ray crystallography. synthetic utility the aldehydes demonstrated conversion to both enantiomers calcium antagonist noremopamil in >98% enantiomeric excess(ee). purity final amines assayed 1H NMR spectroscopy presence...
Healthcare marketing authorization holders are undertaking widespread risk assessment activities following the discovery of dialkyl N-nitrosamines in certain drug substances and products. A contribution to this exercise is kinetic modeling reaction secondary amines with nitrite ion aqueous solution identification conditions where would present a N-nitrosamine formation. Herein, we describe automated experimental nitrosation studies on di-n-butylamine that highlight conservative nature...
It is almost inevitable that any regulatory highlights review at present will be dominated by N-nitrosamines. Therefore, "where are we?" and "what next?" key questions we explore within this review.
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