- Aluminium-Catalysed Oxazolidinone Synthesis and their Conversion into Functional Non-Symmetrical Ureas
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An efficient and practical aluminium-catalysed approach towards a range of functional oxazolidinones is reported. The method is based on cheap and readily available starting materials including terminal and internal (bicyclic) epoxides and phenyl carbamate. The oxazolidinones serve as highly useful synthons for the high yield preparation of non-symmetrical ureas by nucleophilic ring-opening affording the targeted urea compounds with excellent functional group diversity, high regioselectivity and isolated yields up to >99%.
- Laserna, Victor,Guo, Wusheng,Kleij, Arjan W.
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p. 2849 - 2854
(2015/09/28)
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- Direct assembly of 2-oxazolidinones by chemical fixation of carbon dioxide
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The reaction of β- and γ-haloamines with carbon dioxide to give pharmaceutically relevant 2-oxazolidinones and 1,3-dioxazin-2-ones, was found to proceed efficiently in the presence of a base and in the absence of catalyst. After optimization of reaction conditions, the system was successfully expanded to a variety of haloamines, even at multigram scale. The reaction was further studied in silico by DFT calculations. The reaction of β- and γ-haloamines with carbon dioxide to give pharmaceutically relevant cyclic urethanes was found to proceed efficiently in the presence of a base and in the absence of catalyst (see figure). After optimization of reaction conditions, the system was expanded to a variety of haloamines, even at a multigram scale. The reaction was further studied in silico by DFT calculations.
- Niemi, Teemu,Perea-Buceta, Jesus E.,Fernandez, Israel,Alakurtti, Sami,Rantala, Erika,Repo, Timo
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supporting information
p. 8867 - 8871
(2014/07/22)
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- Methyl-thiazoles: A novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in mycobacterium tuberculosis
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InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a Kd of ～13.7 nM, as against the NAD+-bound form of the enzyme.
- Shirude, Pravin S.,Madhavapeddi, Prashanti,Naik, Maruti,Murugan, Kannan,Shinde, Vikas,Nandishaiah, Radha,Bhat, Jyothi,Kumar, Anupriya,Hameed, Shahul,Holdgate, Geoffrey,Davies, Gareth,McMiken, Helen,Hegde, Naina,Ambady, Anisha,Venkatraman, Janani,Panda, Manoranjan,Bandodkar, Balachandra,Sambandamurthy, Vasan K.,Read, Jon A.
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p. 8533 - 8542
(2013/12/04)
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- Synthesis of racemic and chiral Carvedilol starting from corresponding 5-(chloromethyl)oxazolidin-2-one
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The synthesis of racemic Carvedilol ((±)-1) has been achieved starting from 2-(chloromethyl) oxirane ((±)-2) in a four-step sequence. 5-(Chloromethyl) oxazolidin-2-one ((±)-3) and 5-((9Hcarbazol-4-yloxy) methyl) oxazolidin-2-one ((±)-4) are intermediates. A similar sequence starting from (R)- or (S)-2-(chloromethyl)oxirane 2 give corresponding chiral 5-((9Hcarbazol-4-yloxy)methyl) oxazolidin-2-one 4 followed by chiral Carvedilol 1. The synthetic sequence followed avoids the formation of impurity B (bis impurity). This approach can be useful for the preparation of pharmaceutically important moieties containingβ-amino alcohols without formation of bis impurity.
- Anand Kumar,Veera Babu,Rao, Rama Koteshwar,Srinivas, Kumbam,Madhusudhan,Mukkanti
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p. 1430 - 1435
(2012/11/06)
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- 2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: Attenuation of hERG binding and improved HDLc-raising efficacy
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The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27 mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.
- Sweis, Ramzi F.,Hunt, Julianne A.,Sinclair, Peter J.,Chen, Ying,Eveland, Suzanne S.,Guo, Qiu,Hyland, Sheryl A.,Milot, Denise P.,Cumiskey, Anne-Marie,Latham, Melanie,Rosa, Raymond,Peterson, Larry,Sparrow, Carl P.,Anderson, Matt S.
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scheme or table
p. 2597 - 2600
(2011/06/20)
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- 3-halo-5-halomethyl-2-oxazolidinones and their use as microbicides
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A 3-halo-5-halomethyl-2-oxazolidinone, a method of making the same and a method of using the compound as a microbicide and for controlling the growth of at least one microorganism in an aqueous system or on a surface. A process for making 5-halomethyl-2-oxazolidinone utilizing an alkali cyanate and an epihalohydrin.
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- RECYCLIZATION REACTIONS OF SMALL RINGS. 8. SYNTHESIS OF 5-SUBSTITUTED 2-OXAZOLIDONES FROM THIAZOLIDINE-2,4-DIONE AND OXIRANES
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Treatment of oxiranes with thiazolidine-2,4-dione gives N-(2-hydroxypropyl)-thiazolidine-2,4-diones which can recyclize to 5-substituted 2-oxazolidones in basic medium.
- Korotkikh, N. I.,Aslanov, A. F.,Shvaika, O. P.
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p. 915 - 917
(2007/10/02)
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