Sudipta Roy’s Post

𝘛𝘩𝘦 𝘙𝘰𝘶𝘵𝘦 𝘕𝘰𝘵 𝘛𝘢𝘬𝘦𝘯 - 𝘌𝘱𝘪𝘴𝘰𝘥𝘦 5 𝗜𝗻𝘃𝗲𝘀𝘁𝗶𝗴𝗮𝘁𝗶𝗼𝗻 𝗼𝗳 𝘁𝗵𝗲 𝗦𝘆𝗻𝘁𝗵𝗲𝘁𝗶𝗰 𝗦𝘁𝗿𝗮𝘁𝗲𝗴𝗶𝗲𝘀 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗪𝗥𝗡 𝗶𝗻𝗵𝗶𝗯𝗶𝘁𝗼𝗿 𝗛𝗥𝗢𝟳𝟲𝟭 𝗯𝘆 𝗡𝗼𝘃𝗮𝗿𝘁𝗶𝘀 ChemAIRS proposed a feasible 13-step synthetic route (Scheme 1) wherein the final target compound was synthesized through an amide coupling reaction between intermediates 13a and 13b, closely mirroring the methodology reported by Novartis. 𝘔𝘰𝘳𝘦𝘰𝘷𝘦𝘳, 𝘊𝘩𝘦𝘮𝘈𝘐𝘙𝘚 𝘪𝘥𝘦𝘯𝘵𝘪𝘧𝘪𝘦𝘥 𝘢 𝘱𝘰𝘵𝘦𝘯𝘵𝘪𝘢𝘭 𝘳𝘪𝘴𝘬 𝘪𝘯 𝘵𝘩𝘦 𝘧𝘪𝘯𝘢𝘭 𝘴𝘵𝘦𝘱, 𝘴𝘱𝘦𝘤𝘪𝘧𝘪𝘤𝘢𝘭𝘭𝘺 𝘢 𝘱𝘰𝘴𝘴𝘪𝘣𝘭𝘦 𝘴𝘪𝘥𝘦 𝘳𝘦𝘢𝘤𝘵𝘪𝘰𝘯 𝘢𝘴 𝘥𝘦𝘱𝘪𝘤𝘵𝘦𝘥 𝘪𝘯 𝘍𝘪𝘨𝘶𝘳𝘦 1. Notably diverging from the existing patent, ChemAIRS suggested a 3-step synthesis for the key intermediate 13b. This procedure commenced with a Suzuki coupling reaction to form the chloropyrimidine derivative 2b, which was subsequently transformed into the corresponding methyl ester 3a via palladium-catalyzed carbonylation. 𝗥𝗲𝘃𝗶𝘀𝗲𝗱 𝗦𝘆𝗻𝘁𝗵𝗲𝘁𝗶𝗰 𝗦𝘁𝗿𝗮𝘁𝗲𝗴𝘆 𝘁𝗼 𝗠𝗶𝗻𝗶𝗺𝗶𝘇𝗲 𝗥𝗲𝗮𝗰𝘁𝗶𝗼𝗻 𝗥𝗶𝘀𝗸𝘀 Acknowledging a risk associated with the final step of Scheme 1, which involved an amide coupling reaction between intermediate 13a and pyrimidine-carboxylic acid 13b, we tasked ChemAIRS to propose an alternative approach as illustrated in Scheme 2. In this revised scheme, the pyrimidine moiety was introduced earlier in synthesis via an amide coupling reaction between 11a and 11b, followed by a demethylation step to yield 13b. In the final step, trifluoromethylaniline 13a reacted with the intermediate 13b, a strategy intended to minimize the risk of the side reaction mentioned in Figure 1. In conclusion, the ChemAIRS Retrosynthesis tool demonstrated its robust capability in identifying potential risks and proposing innovative solutions. Its capability to deviate from existing patents and suggest a synthesis for key intermediates underscores its value in accelerating synthetic organic chemistry projects and ensuring successful outcomes. #HRO761 #reactioninformatics #retrosynthesis

If you had to attach a vinyl group to an aromatic ring, how would you do it? The first method that comes to my mind is the Stille vinylation using tributylvinyl stannane. But it uses one of our favourite toxic heavy metals – tin. Maybe a better approach is to do a Sonogashira with TMS-protected acetylene followed by a desilylation – partial reduction protocol. If anyone is counting that is three steps to attach a group with a molecular weight of 27 – you might say not the most atom efficient. No doubt there are better methods available but I’m on a train and freewheeling right now. The optimal approach would be to do a direct coupling between an aryl halide and ethylene - of course, the Nobel Prize winning Heck reaction! OK – nothing new here, but high pressures of ethylene gas can be required limiting practicality. If there was a better way to do this reaction using a non-gaseous source of ethylene you would use it, right? 56 years after Heck reported the use of ethylene in his namesake reaction, a procedure using an ethylene surrogate has been disclosed: https://lnkd.in/ev8bghTF. An academic-industrial partnership (which I do my best to champion: https://lnkd.in/efjFibuE) has identified the use of tetraethylammonium bromide (a common commercially available phase transfer catalyst) as a ethylene precursor in Heck reactions to vinylate a set of simple aryl bromides. The reaction conditions are typical of the Heck reaction and the ‘greener’ solvent CPME is also effective in place of toluene – a nice find. As it currently stands the reaction does have a few drawbacks included limited functional group tolerance, a seemingly strong dislike of steric hindrance and a large fall off in yield on 1 mmol scale – something the authors readily acknowledge and are working hard to overcome, no doubt. If you are working on a discovery-type project with sub-mmol scale reactions and a vinylation is required, I would urge you to give this new method a go before you reach for the tin! #OrganicSynthesis #MedicinalChemistry #Pharmaceuticals #DrugDiscovery #Methodology

Today in Nature Communications we report the regioselective hydroamination of unactivated olefins with diazirines. Over 50 examples highlight excellent functional group tolerance and permit the rapid synthesis of alkyl amines, hydrazines, and heterocycles. https://lnkd.in/eYbDfb-W The scope includes the late-stage amination of 14 terpene natural products and [1.1.1]propellane, while the synthetic applications demonstrate the target-oriented synthesis of numerous pharmaceuticals such as mecamylamine, neramexane, and a splicing modulator. A novel synthesis of our bis-15N diazirine enables the isotopic labeling of any of our past and present diazirine aminations without the need for redesign of the synthetic routes. Congrats to Qingyu Xing, Preeti Chandrachud, PhD, and Khalilia Tillett.

This paper reports a metallaphotoredox multicomponent amination strategy employing 3,3,3-trifluoropropene, nitroarenes, tertiary alkylamines & carboxylic acids. It offers notable advantages of accessibility and cost-effectiveness of starting materials, high levels of chemo- and regioselectivity & modularity.

Here Hoare et al describes the use of methionine alkylation to quantify methionine oxidation via mass spectrometry 🎯 Summary: Hoare et al has developed a modification to Methionine Oxidation by Blocking (MObB) for methionine oxidation quantifaction. Which they have termed Methionine Oxidation by Blocking with Alkylation (MObBa) for selective alkylation and quantitation of unoxidized methionines by iodoacetamide (IAA). Hoare et al note there are several advantages to this approach 18O-H2O2, IAA is significantly less expensive, commonly available, and amenable to standard proteomic workflow Futhermore 18O- and 16O-labeled peptides vary in mass by only 2 Da, their spectral isotopic envelopes are overlapped, making analysis challangeing. Hoare et al have noted that the alkylation of methionines is a relatively slow reaction, occurring over the course of 3 days at 37 °C. The slow reaction rate not only adds to the overall analysis time but may also lead to accumulation of oxidation and other modifications prior to alkylation. Just something to ba aware of https://lnkd.in/eCihgrU2 #massspectrometry #massspec #chemistry #oxidation #pharma #biotherapeutics

DMPE (14:0 PE), or 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine, is a phospholipid. This compound is made up of a glycerol backbone, with two myristoyl fatty acid chains attached. The "14:0" designation denotes that the fatty acid chains are myristoyl, meaning they consist of 14 carbon atoms with no double bonds. This specific phospholipid is of interest in biological and chemical research due to its role in cellular membranes and its potential applications in encapsulation and drug delivery systems. #DMPE #Dimyristoyl #encapsulation #membranes #drug #myristoyl #fatty #acid #chains https://lnkd.in/gKnuc_Sd

Adding an alkyl or an alkenyl group to a molecule can change its properties drastically. Be they small or bulky, short- or long-chain, the changes brought about by the introduction of these hydrocarbon groups are what makes them interesting all the way from pharmaceutical chemistry to materials science. However, the reagents for these transformations are often difficult to handle, not least due to their often significant health hazards. In their Review, Johanna Templ and Michael Schnürch (Technische Universität Wien) provide a comprehensive overview of an alternative substance class that can be used for this purpose: quaternary #ammonium salts, QAS. These non-toxic and easy-to-handle #reagents can be used in various #alkylation strategies, broadly classified into metal-free nucleophilic substitutions and transition metal-catalyzed transformations. Despite their benefits and many successful examples, the full potential of QAS is not yet explored. Making a convincing case for change, the authors provide concrete guidance for researchers. Our Pick of the Week, published #OpenAccess in Chemistry – A European Journal #ChemEurJ: “Strategies for using Quaternary Ammonium Salts as Alternative Reagents in Alkylations” https://ow.ly/gVSV50Rzz7G

"Top Types of Pyridine Compounds with Examples: Key Derivatives and Their Uses in Chemistry" #Pyridine #OrganicChemistry #ChemicalCompounds #PyridineDerivatives #PharmaceuticalChemistry #ChemicalSynthesis #Quinoline #Isoquinoline #ChemistryEducation #LaboratoryScience #ChemicalIndustry #ResearchAndDevelopment #ScientificResearch #OrganicSynthesis #MolecularChemistry https://lnkd.in/gjtCMtqj

🌐 Chemical Name: Phenyl Dichlorophosphate 🖊 CAS: 770-12-7 ✏ EINECS: 212-468-4 🖌 Molecular Formula: C₆H₅Cl₂O₄P 🖍 Molecular Weight: 201.98 🔖 Properties: Phenyl Dichlorophosphate is a clear colourless to very slightly brown liquid. 📝 Applications: Reagent for preparation of phosphate diesters. Phenyl dichlorophosphate is used in the preparation of symmetrical phosphate diesters. It is used as a phosphorylating agent for alcohols and amines. It is also involved in the preparation of phenylphosphoro di-(1-imidazolidate) and 2-phenyl-bis-triazoloylphosphate, which is used in peptide synthesis. It plays a vital role in the Pfitzner-Moffatt oxidation which involves oxidation of alcohols to the corresponding aldehydes and ketones. Furthermore, it is utilized in Beckmann rearrangement for the preparation of N-phenylacetamide from acetophenone oxime.

HPGM is an important intermediate and plays a key role in the enzymatic synthesis of amoxicillin. Early HPG was derived from chemical synthesis, but now the new synthesis method is to make it through enzyme synthesis. This process is more environmentally friendly, green and energy-saving. #Hydroxyphenylglycine #hpg #hpgm #amoxicillin #enzyme