- A novel synthetic approach to the racemic Neuraminidase inhibitor Peramivir
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An advanced intermediate in the synthesis of the racemic Neuraminidase inhibitor Peramivir was synthesised in a new and versatile manner starting from a stereoselective 1,3-dipolar cycloaddition reaction between the nitrile oxide deriving from 2-ethylbutanal and the commercially available and inexpensive bicyclo[2.2.1]hepta-2,5-diene. The reaction mainly afforded the exo-isoxazolino-norbornene derivative from which the oxidative cleavage of the carbon[sbnd]carbon double bond followed by subsequent dehydration led to the corresponding anhydride intermediate. Amines and alcohols were used as nucleophiles for opening the anhydride, with amines providing the better results. Both the monoester–monoacid and the monoester–monoamide were transformed into the monoester–monoamino intermediate from which the synthesis continued using previously published methods. In the best protocol, the total yield of this key intermediate was increased up to 17% from bicyclo[2.2.1]hepta-2,5-diene.
- Erba, Emanuela,La Rosa, Concetta
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- New Strategy of Synthesis of Peramivir Analogues as Potential Neuraminidase Inhibitors
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Highly functionalised potential neuraminidase (NA) inhibitors, analogues of peramivir, were synthesised via a new and versatile method starting from a stereoselective 1,3-dipolar cycloaddition reaction between the nitrile oxide derived from 2-ethylbutanal and the commercially available and inexpensive cyclopentadiene and 1,3-cyclohexadiene, which afforded the isoxazolino-cyclopentene or cyclohexene intermediates, respectively. The subsequent reaction of the C=C bond in different conditions allowed the functionalisation of the five (or six) membered carbon nucleus. Further functionalised derivatives displaying an amino and a hydroxyl group were achieved via the final opening of the isoxazoline ring.
- Bartolotta, Roberta,La Rosa, Concetta,Nava, Donatella
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- (1S, 2S, 3S, 4R)-3-Y(1S)-1-ACETYLAMINO-2-ETHYL-BUTYL¨-4-GUANIDINO-2- HYDROXYL-CYCLOPENTYL-1-CARBOXYLIC ACID HYDRATES AND PHARMACEUTICAL USES THEREOF
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The present invention relates to (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrates compounds, preparing methods thereof, pharmaceutical compositions containing said compounds and preparing methods thereof, and the clinical uses of said compounds as neuramidinase inhibitors for anti-influenza.
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Page/Page column 10
(2010/06/15)
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- Stereoselective total synthesis of racemic BCX-1812 (RWJ-270201) for the development of neuraminidase inhibitors as anti-influenza agents
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A convergent and versatile racemic total synthesis of the anti-influenza agent BCX-1812 (RWJ-270201) was accomplished on the basis of a sequence of stereoselective reactions. Despite intensive research to develop neuraminidase inhibitors to treat infections due to influenza, currently available agents are still in the need of optimization with respect to selectivity and potency, as well as to minimize adverse effects. Our synthetic approach, introduced in this report, is highly exploitable for further derivatization due to flexibility that will eventually accommodate diversified substituents. In addition, the size of the core ring can be varied depending on the size of the diene used for the preparation of the key cycloadduct 10 using an acylnitroso-based hetero-Diels-Alder reaction. Elaboration of 10 to methyl ester 14 followed by a precedented [3+2] dipolar cycloaddition gave bicyclic isoxazoline 17 in a regio- and stereoselective fashion. Incorporation of the peripheral guanidino group and subsequent deprotection provided the target molecule. The details of the synthesis are described herein.
- Mineno, Tomoko,Miller, Marvin J.
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p. 6591 - 6596
(2007/10/03)
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