- Kilogram-Scale Synthesis of 2′- C-Methyl- arabino-Uridine from Uridine via Dynamic Selective Dipivaloylation
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We report a practical 3′,5′-diprotection strategy suitable for the kilogram-scale preparation of 2′-C-methyl-arabino-uridine, a key intermediate in the synthesis of the HCV NS5B inhibitor uprifosbuvir. Starting from uridine, dipivaloylation afforded an ~2:1 mixture of 3′,5′- and 2′,5′-dipivaloyluridine. Subjecting this mixture to TEMPO/bleach oxidation promoted a dynamic acylation migration-selective oxidation to afford the 2′-ketone in 65% yield. Alternatively, treatment with 1 equiv of BF3 etherate led to the crystallization-driven equilibration and precipitation of 3′,5′-dipivaloyluridine·BF3 complex in a >50:1 ratio. After salt break, this mixture was oxidized in the presence of TEMPO/AcOOH to afford the 2′-ketone in 90% yield. Subsequent α-facial-selective methylation with MeMgBr/MnCl2 afforded 3′,5′-dipivaloylated 2′-C-methyl-arabino-uridine 12. This three-step process was successfully demonstrated on a multikilogram scale to afford the key intermediate for the manufacture of uprifosbuvir.
- Calabria, Ralph,Campeau, Louis-Charles,Chung, John Y. L.,Dalby, Stephen M.,Davis, Tyler A.,He, Cyndi Q.,Kassim, Amude M.,Limanto, John,Simmons, Bryon,Song, Zhiguo J.,Wright, Timothy J.
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- RELEASABLE CONJUGATES
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The present application provides compounds of Formula (B), or pharmaceutically acceptable salts thereof, wherein D is a residue of a biologically active drug, which underdo hydrolysis under physiological conditions to release the biologically active drug and which are useful in the treatment of disorders that could be beneficially treated with the drug.
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Page/Page column 178; 179
(2018/09/28)
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- Regioselective Mitsunobu Reaction of Partially Protected Uridine
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Mitsunobu reaction of partially acylated uridine proceeds with high regioselectivity for intramolecular SN2 anhydro linkage closuring. Under the reaction conditions, an isomeric mixture of diacyl uridine derivatives with either free 2′- or 3′-hydroxyl group was transformed into a single cyclonucleosidic product, 2,2′-anhydro-3′,5′-di-O-acyluridine. This paper presents a possible mechanism of the reactions, the explanation of observed phenomenon based on semiempirical and density functional theory (DFT) calculations and possible utility of this synthetic pathway.
- Szlenkier, Maurycy,Kamel, Karol,Boryski, Jerzy
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p. 410 - 425
(2016/08/05)
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- REGIOSELECTIVE PROTECTION OF CARBOHYDRATE DERIVATIVES. PART. 20. SIMPLE, EFFICIENT 2'-O-DEACYLATION OF FULLY ACYLATED PURINE AND PYRIMIDINE RIBONUCLEOSIDES THROUGH tert-BUTOXIDE
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A simple treatment of fully aroylated purine and pyrimidine ribonucleosides with pulverized potassium tert-butoxide in tetrahydrofuran (THF) or dichloromethane under a controlled condition gave a mixture of the corresponding di-O-aroyl derivatives in which 2'-OH derivatives are preponderant over 3'-OH derivatives; 3',5'-di-O-benzoyluridine, N4,3',5'-tribenzoylcytidine, N4,3',5'-tri-O-toluoylcytidine, N2,3',5'-tribenzoylguanosine, and N2,isobutyryl-3',5'-di-O-benzoylguanosine were obtained crystalline in 80 percent, 78 percent, 72 percent, 67 percent, and 65 percent yields, respectively.
- Nishino, Shigeyoshi,Takamura, Hatsuko,Ishido, Yoshiharu
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p. 1995 - 2004
(2007/10/02)
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- Partial Protection of Carbohydrate Derivatives. Part 4. Regioselective 2'-O-Deacylation of Fully Acylated Purine and Pyrimidine Ribonucleosides with Hydroxylaminium Acetate
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Like hydrazine hydrate, hydroxylamine was found to be useful for the regioselective 2'-O-deacylation of fully acylated purine and pyrimidine ribonucleosides as its salt with acetic acid; the partial O-deacylation reactions (which were not accompanied by undesirable discolouration as happens with hydrazine hydrate) gave the corresponding di-O-acylribonucleosides in superior yields; e.g. 2',3'-di-O-benzoyladenosine (74percent yield), 3',5'- (64percent yield) and 2',5'-di-O-benzoyl-N6-benzyladenosine (63percent yield on performing the reaction in ethanol), N2,3',5'-tri-O-benzoylguanosine (66percent yield), N2,2',5'-tri-isobutyrylguanosine (48percent yield), and 3',5'-di-O-benzoyluridine (61percent yield) were obtained using hydroxylaminium acetate in pyridine.Treatment of fully acetylated ribonucleosides with an excess of hydroxylaminium acetate gave the corresponding 5'-O-acetylribonucleosides in quantitative yields.The excellent regioselectivity observed in the present partial O-decyclation was confirmed on the basis of chromatographic separation; the mixtures of di-O-acylribonucleosides, which had already been equilibrated in pyridine, were re-equilibrated on the silica gel during separation, e.g. a 70 : 30 mixture of 3',5'- and 2',5'-di-O-benzoyladenosine was completely converted into the former based on 1H n.m.r spectroscopy.The acetates of 9-β-D-xylo- and -arabino-furanosyladenine were also found to give predominantly the corresponding 3',5'-diacetates on hydroxylaminolysis.
- Ishido, Yoshiharu,Sakairi, Nobuo,Okazaki, Kei,Nakazaki, Nobuo
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p. 563 - 573
(2007/10/02)
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