- Synthesis and Antiviral Evaluation of TriPPPro-AbacavirTP, TriPPPro-CarbovirTP, and Their 1′,2′-cis-Disubstituted Analogues
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Herein we describe the synthesis of lipophilic triphosphate prodrugs of abacavir, carbovir, and their 1′,2′-cis-substituted carbocyclic analogues. The 1′,2′-cis-carbocyclic nucleosides were prepared by starting from enantiomerically pure (1R,2S)-2-((benzyloxy)methyl)cyclopent-3-en-1-ol by a microwave-assisted Mitsunobu-type reaction with 2-amino-6-chloropurine. All four nucleoside analogues were prepared from their 2-amino-6-chloropurine precursors. The nucleosides were converted into their corresponding nucleoside triphosphate prodrugs (TriPPPro approach) by application of the H-phosphonate route. The TriPPPro compounds were hydrolyzed in different media, in which the formation of nucleoside triphosphates was proven. While the TriPPPro compounds of abacavir and carbovir showed increased antiviral activity over their parent nucleoside, the TriPPPro compounds of the 1′,2′-cis-substituted analogues as well as their parent nucleosides proved to be inactive against HIV.
- Weising, Simon,Sterrenberg, Vincente,Schols, Dominique,Meier, Chris
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p. 1771 - 1778
(2018/09/11)
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- Abacavir intermediate and method for purifying same
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The invention discloses an abacavir intermediate and a method for purifying the same. The method includes heating mixtures with abacavir intermediate crude products, purified water and water-soluble organic solvents until the abacavir intermediate crude products are completely dissolved so as to obtain mixed liquid; carrying out cooling and crystallization treatment on the mixed liquid; carrying out filtering and drying treatment after crystallization treatment is carried out so as to obtain abacavir intermediate pure products. A structural formula of the abacavir intermediate is shown as a formula IV. The abacavir intermediate and the method have the advantage that the method is easy and convenient to implement and is suitable for industrial production.
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Paragraph 0079-0080
(2018/03/26)
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- PROCESS FOR THE PREPARATION OF AMINO ALCOHOL DERIVATIVES OR SALTS THEREOF
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The present invention relates to a process for the preparation of amino alcohol derivatives or salts thereof. In particular the present invention relates to process for the preparation of amino alcohol derivatives or salts thereof which may be used as intermediates in the preparation of HIV reverse transcriptase inhibitors, more preferably Carbovir and Abacavir. The present invention more specifically relates to a process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula IIIa. The present invention also specifically relates to process for the preparation of Abacavir sulfate of Formula II using compound of Formula IIIa prepared according to the process of the present invention.
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Paragraph 0056; 0057; 0058; 0059; 0060
(2017/09/02)
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- Enantioselective and Regiodivergent Addition of Purines to Terminal Allenes: Synthesis of Abacavir
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The rhodium-catalyzed atom-economic asymmetric N-selective intermolecular addition of purine derivatives to terminal allenes is reported. Branched allylic purines were obtained in high yields, regioselectivity and outstanding enantioselectivity utilizing a Rh/Josiphos catalyst. Conversely, linear selective allylation of purines could be realized in good to excellent regio- and E/Z-selectivity with a Pd/dppf catalyst system. Furthermore, the new methodology was applied to a straightforward asymmetric synthesis of carbocyclic nucleoside abacavir.
- Thieme, Niels,Breit, Bernhard
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supporting information
p. 1520 - 1524
(2017/02/05)
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- Enantioselective synthesis of the carbocyclic nucleoside (-)-abacavir
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An enantiopure β-lactam with a suitably disposed electron withdrawing group on nitrogen, participated in a π-allylpalladium mediated reaction with 2,6-dichloropurine tetrabutylammonium salt to afford an advanced cis-1,4-substituted cyclopentenoid with both high regio- and stereoselectivity. This advanced intermediate was successfully manipulated to the total synthesis of (-)-Abacavir.
- Boyle, Grant A.,Edlin, Christopher D.,Li, Yongfeng,Liotta, Dennis C.,Morgans, Garreth L.,Musonda, Chitalu C.
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p. 1870 - 1876
(2012/05/04)
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- Novel salts of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol
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The present invention relates to novel salts of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1 -methanol of Formula I or solvates or hydrates thereof, wherein M represents hemimalonate, malonate, hemioxalate, oxalate, hydrobromide, dihydrobromide, hemimaleate, maleate.
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Page/Page column 9
(2011/04/25)
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- Process for the Preparation of Abacavir
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Process for removal of the amino protective group of a N-acylated [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-cyclopent-2-enyl]methanol of formula (II) where R═H or a (C1-C4)-alkyl, using an inorganic base in a mixture of water and alcohol, to yield abacavir or its salts. The process proceeds very fast and the product can be obtained in high yield and purity.
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Page/Page column 3-4
(2010/02/16)
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- PREPARATION OF SYNTHETIC NUCLEOSIDES VIA π-ALLYL TRANSITION METAL COMPLEX FORMATION
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This invention provides highly regioselective and stereoselective processes for preparing synthetic nucleosides. A process for the preparation of synthetic nucleosides is provided that comprises a) preparing a bicycloamide derivative, b) reacting the bicycloamide derivative with a nucleic acid base or heterocyclic base or salt thereof in the presence of a transition metal catalyst to form a cyclopentenecarboxamide, and c) cleaving a carboxamide group from the cyclopentenecarboxamide to form the synthetic nucleoside. The processes according to the invention can be used for the synthesis of a variety of anti-viral agents, including Abacavir, Carbovir, and Entecavir, as well as derivatives thereof.
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Page/Page column 44; 47
(2009/04/25)
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- Process for the preparation of abacavir
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Process for the preparation of abacavir starting from compound of formula (IV) where R1 is a (C1-C4)-alkyl radical comprising first reacting said compound (IV) with anhydrous hydrochloric acid/(C1-C6)-alcohol, and then with tri(C1-C4)-alkyl orthoformate, in the absence of water, followed by reacting the compound obtained with cyclopropylamine and hydrolysing the compound obtained to yield abacavir or its salts.
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Page/Page column 7
(2008/12/06)
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- Process for the preparation of abacavir
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Process for removal of the amino protective group of a N-acylated {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-cyclopent-2-enyl}methanol of formula (II) where R = H or a (C1-C4)-alkyl, using an inorganic base in a mixture of water and alcohol, to yield abacavir or its salts. The process proceeds very fast and the product can be obtained in high yield and purity.
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Page/Page column 5
(2008/06/13)
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- Enantioselective syntheses of carbanucleosides from the Pauson-Khand adduct of trimethylsilylacetylene and norbornadiene
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(Chemical Equation Presented) A new enantioselective approach to carbanucleosides from Pauson-Khand (PK) adduct 1 is disclosed. The chiral cyclopentenone 1 is readily accessible in enantiomerically pure form via PK reaction of trimethylsilylacetylene and norbornadiene using N-benzyl-N- diphenylphosphino-tert-butyl-sulfinamide as a chiral P,S ligand. (-)-Carbavir and (-)-Abacavir were enantioselectively synthesized starting from (-)-1. The key steps of the sequence are a photochemical conjugate addition of a hydroxymethyl radical, a retro-Diels-Alder reaction, and a palladium catalyzed allylic substitution to introduce the nucleobase.
- Vazquez-Romero, Ana,Rodriguez, Julia,Lledo, Agusti,Verdaguer, Xavier,Riera, Antoni
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supporting information; experimental part
p. 4509 - 4512
(2009/05/11)
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- Process for the preparation of abacavir
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A process for the preparation of Abacavir of formula 1 and its sulfate salt comprising the reaction of a compound of formula 6 with cyclopropyl amine.
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Page/Page column 5
(2010/11/28)
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- PROCESS FOR THE PREPARATION OF (1S, 4R) -CIS-4-‘2-AMINO-6CHLORO-9H-PURIN-9-YL!-2-CYCLOPENTENE-1-METHANOL
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A process for preparing a chloropurine compound of formula (I) or a derivative thereof, which comprises ring closure of the compound of formula (VII) or a derivative thereof in the presence of catalytic acid and at least one equivalent of a formate derivative.
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Page/Page column 7-8
(2008/06/13)
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- NOVEL CRYSTALLINE FORMS OF ABACAVIR SULFATE
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The present invention relates to novel crystalline forms of abacavir sulfate, to processes for their preparation and to pharmaceutical compositions containing them.
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- Pharmaceutical compositions
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The present invention relates to pharmaceutical compostions of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino}-9H-purin-9-yl]-2-cyclopentene-1-methanol (1592U89).
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- LIQUID PHARMACEUTICAL FOR ORAL DELIVERY
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A liquid pharmaceutical for oral delivery wherein at the time of use, a solid unit dosage form is added to the liquid wherein the unit dosage form is comprised of a substrate soluble in the liquid and a particulate pharmaceutically active material in a pharmaceutically effective amount. At the time of use, the unit dosage form is added to the liquid, without requiring measurement of the liquid, and the entire liquid is consumed to provide for oral delivery of the pharmaceutically effective amount of material.
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- An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy
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A general and efficient synthesis of carbocyclic and hexenopyranosyl nucleosides has been developed. The strategy combines three key transformations: an asymmetric aldol addition to establish the relative and absolute configuration of the pseudosugar, a ring-closing metathesis to construct the pseudosugar ring, and a Trost-type palladium(0)-mediated substitution to assemble the pseudosugar and the aromatic base. Carbovir, abacavir, and their 2'-methyl derivatives as well as hexenopyranosyl nucleoside analogues have been prepared by this sequence.
- Crimmins,King,Zuercher,Choy
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p. 8499 - 8509
(2007/10/03)
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- An efficient, scalable synthesis of the HIV reverse transcriptase inhibitor Ziagen (1592U89)
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Ziagen, (1S, cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol, was synthesized from (1S,4R)-azabicyclo[2.2.1]hept- 5-en-3-one by efficient processes which bypass problematic steps in earlier routes. 2-Amino-4,6-dichloro-5-formamidopyrimidine is a key intermediate which makes possible an efficient construction of the purine from a chiral cyclopentenyl precursor.
- Daluge, Susan M.,Martin, Michael T.,Sickles, Barry R.,Livingston, Douglas A.
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p. 297 - 327
(2007/10/03)
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- Solid-phase synthesis of carbocyclic nucleosides.
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[formula: see text] An efficient solid-phase synthesis of carbocyclic nucleosides has been developed. The key step is the palladium-catalyzed coupling of a purine derivative to a resin-bound allylic benzoate. The resulting products may be further functionalized on the solid phase. Acidic cleavage affords carbocyclic nucleosides, a class of compounds with demonstrated biological activity and substantial current interest.
- Crimmins,Zuercher
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p. 1065 - 1067
(2007/10/03)
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- Chloropyrimidine intermediates
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The present invention is related to a process of making of 2,6-diaminopurines wherein the 6-amino group is substituted by R4 and R5, by reacting a compound of formula (VI) STR1 with an excess of amine NHR4 R5.
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- Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues
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The hydroxylactones 4a-b (both available in optically pure form from biocatalytic processes) have been used in the preparation of carbovir, 1592U89, and their six-membered ring analogues.
- Olivo, Horacio F.,Yu, Jiaxin
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p. 391 - 392
(2007/10/03)
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