Synthesis and pharmacology of metabolically stable tert-butyl ethers of morphine and levorphanol

Mohacsi, Erno; Leimgruber, W.; Baruth, Herman W.

doi:10.1021/jm00352a037

Cited by 12 publications

(10 citation statements)

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“…These compounds were synthesized from cyclohexanone in a ten-step procedure [ 30 ]. Levorphan ( 18 ), which has an R -absolute configuration at all of its asymmetric centres, is a potent opioid receptor agonist with an approximately seven-fold higher affinity than morphine [ 31 ]. Dextrometorphan ( 19 ), which is the (9 S ,13 S ,14 S )-isomer, has no analgesic activity, but is commonly used as cough suppressant.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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“…The nascent tert-butyl cation (51) derived from 6e either combines with the adjacent carboxylate anion to give the desired tert-butyl ester 52 and DMF (5), or loses a proton to give 2-methylpropene (53). Analogously, phenol (32) combines via its corresponding phenolate anion with the nascent tert-butyl cation ( 51) on heating with excess 7e at 100-110 °C to give the corresponding tert-butyl phenyl ether (54) in 39% yield, 55,56 as well as DMF ( 5) and 2-methylpropene (53) (Scheme 12). Further applications of 7e in the conversion of carboxylic acids 1 into tert-butyl esters can be found in the literature.…”

Section: Scheme 11mentioning

confidence: 99%

“…69 Likewise, carboxylic acids 1, as well as phenols 16, can be reacted with O-tert-butyl-N,N¢-diisopropylisourea [Me 3 COC(=Ni-Pr)NHi-Pr] to provide the corresponding tert-butyl esters or ethers, respectively, in high yields. 72 Because the methylene group in derivatives of neopentyl alcohol (55), such as in the iminium cation 6d, reacts very slowly 73 with nucleophilic carboxylate anions 14, Eschen-moser introduced DMF dineopentyl acetal 7d, which on the addition of free carboxylic acids 1 and free alcohols 2 gives an equilibrium between iminium cations 6d and 6 resulting nearly exclusively in the formation of the desired corresponding esters 4, DMF (5), and free neopentyl alcohol (55) (Scheme 13). 39 Phenolate anions 17 of more acidic phenols 16 react analogously with the iminium cation 6 to give the corresponding phenyl ethers 18 [cf.…”

Section: Scheme 11mentioning

confidence: 99%

Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals

Vorbrüggen¹

2008

Synlett

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The esterification and etherification of unhindered, as well as severely hindered, carboxylic acids and phenols with basic amide acetals, such as N,N-dimethylformamide dimethyl acetal, and their side reactions are discussed. Modified procedures are described in which these side reactions are avoided to achieve high or near quantitative yields of the desired corresponding methyl esters or phenol methyl ethers. On the addition of N,N-dimethylformamide dimethyl acetal, solutions of 4-nitrobenzoic acid in basic solvents, such as tetrahydrofuran or 1,4-dioxane, form precipitates of the corresponding iminium carboxylates, which give near quantitative yields of the desired methyl 4-nitrobenzoate, as well as N,Ndimethylformamide and methanol.

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“…Unfortunately, many diazoalkanes have a reputation as being toxic and energetic, limiting their use and often forcing researchers to form these reagents in situ to avoid issues with handling . Other reagents that undergo symbiotic activation include imidazole carbamates with structures like 2 , , alkoxy-λ 6 -sulfanenitriles like 3 , some amide acetals (like 4 and 5 ), 1,3,5- O -benzyl triazines like 6 , and isoureas like 7 . Most of these reagents require heating to effect their esterifications, usually in refluxing benzene or toluene solvent, with the exception being the isoureas which provide some esters at room temperature.…”

Section: Introductionmentioning

confidence: 99%

Ester Formation via Symbiotic Activation Utilizing Trichloroacetimidate Electrophiles

et al. 2019

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Trichloroacetimidates are useful reagents for the synthesis of esters under mild conditions that do not require an exogenous promoter. These conditions avoid the undesired decomposition of substrates with sensitive functional groups that are often observed with the use of strong Lewis or Brønsted acids. With heating, these reactions have been extended to benzyl esters without electron donating groups. These inexpensive and convenient methods should find application in the formation of esters in complex substrates.

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Synthesis and pharmacology of metabolically stable tert-butyl ethers of morphine and levorphanol

Cited by 12 publications

References 0 publications

A Review of Molecular Imaging of Glutamate Receptors

A Review of Molecular Imaging of Glutamate Receptors

Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals

Ester Formation via Symbiotic Activation Utilizing Trichloroacetimidate Electrophiles

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