- Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane-Sodium Iodide-Promoted Vorbrüggen Glycosylation
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By simple combination of water and sodium iodide (NaI) with chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water)
- Mear, Sarah Jane,Nguyen, Long V.,Rochford, Ashley J.,Jamison, Timothy F.
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p. 2887 - 2897
(2022/02/07)
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- Multienzymatic cascade synthesis of an enantiopure (2R,5R)-1,3-oxathiolane anti-HIV agent precursor
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An enantiopure (2R,5R)-1,3-oxathiolane was obtained using a multienzymatic cascade protocol. By employing a combination of surfactant-treated subtilisin Carlsberg and Candida antarctica lipase B, the absolute configuration of the resulting 1,3-oxathiolane ring was efficiently controlled, resulting in an excellent enantiomeric excess (>99%). This enantiopure 1,3-oxathiolane derivative is a key precursor to anti-HIV agents, such as lamivudine, through subsequent N-glycosylation.
- Ren, Yansong,Hu, Lei,Ramstr?m, Olof
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- METHODS FOR THE TREATMENT OF HEPATITIS B AND HEPATITIS D VIRUS INFECTIONS
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It is disclosed a method for treating hepatitis B virus infection or hepatitis B virus/hepatits delta virus co-infection, the method comprising administering to a subject in need of such treatment a first pharmaceutically acceptable agent that comprises at least one phosphorothioated nucleic acid polymer and a second pharmaceutically acceptable agent that comprises at least one nucleoside/nucleotide analog HBV polymerase inhibitor.
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- Efficient asymmetric synthesis of lamivudine via enzymatic dynamic kinetic resolution
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The anti-HIV nucleoside lamivudine was asymmetrically synthesized in only three steps via a novel surfactant-treated subtilisin Carlsberg-catalyzed dynamic kinetic resolution protocol. The enantiomer of lamivudine could also be accessed using the same protocol catalyzed by Candida antarctica lipase B.
- Hu, Lei,Schaufelberger, Fredrik,Zhang, Yan,Ramstroem, Olof
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p. 10376 - 10378
(2013/10/22)
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- OPTICAL RESOLUTION OF SUBSTITUTED 1, 3-OXATHIOLANE NUCLEOSIDES
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Cis(±)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone is reacted with S(+)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate in methanol to obtain diastereomeric compounds. The diastereomeric compounds are subjected to selective crystallization to obtain (2R-Cis)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate. (2R-Cis)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate is treated with hydrochloric acid in water to obtain (2R-cis)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone.
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Page/Page column 5
(2011/10/13)
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- AN IMPROVED PROCESS FOR THE MANUFACTURE OF LAMIVUDINE
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The present invention relates to an improved process for the Manufacture of Lamivudine. A process for the preparation of essentially enantiomerically pure (-)-[2R, 5S]-4-amino-1-[2- (hydroxymethyl)-1,3-oxathiolan-5-y1]-2(1H)-pyrimidin-2-one of formula (I), from L-menthyl glyoxylate is described. Also provided is a process for preparation of (+)-1- (2R/S-Cis)-4-amino-1-[(2-hydroxymethyl)-1,3-oxathiolan-5-y1]-2(1H)-pyrimidin-2-one of formula (XII), from L-menthyl glyoxylate.
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Page/Page column 14; 18-19
(2011/12/02)
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- A PROCESS FOR STEREOSELECTIVE SYNTHESIS OF LAMIVUDINE
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The present invention discloses a process for stereoselective synthesis of Lamivudine comprising the following steps: (a) performing a glycosylation reaction between the compound of formula (I) and cytosine or protected cytosine, and separating the reaction product by recrystallization to obtain the intermediate of formula (II); and (b) deprotecting the intermediate of formula (II) to obtain Lamivudine.
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Page/Page column 13
(2010/04/24)
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- OPTICAL RESOLUTION OF SUBSTITUTED 1.3-OXATHIOLANE NUCLEOSIDES
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Cis(±)- 4-Amino-1 -[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1 H)- pyrimidinone is reacted with S(+)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate in methanol to obtain diastereomeric compounds. The diastereomeric compounds are subjected to selective crystallization to obtain (2R-Cis)-4-Amino-1-[2- (hydroxymethyl)-i,3-oxathiolan-5-yl]-2(1 H)-pyrimidinone 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate. (2R-Cis)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5- yl]-2(1 H)-pyrimidinone 1,1 '-binaphthyl-2,2'-diyl hydrogen phosphate is treated with hydrochloric acid in water to obtain (2R-cis)-4-Amino-1-[2-(hydroxymethyl)- 1,3-oxathiolan-5-yl]-2(1 H)-pyrimidinone.
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Page/Page column 13-14
(2010/07/02)
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- A novel method for large-scale synthesis of lamivudine through cocrystal formation of racemic lamivudine with (S)-(-)-1,1′-Bi(2-naphthol) [(S)-(BINOL)]
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A large-scale synthesis of (-)-[2R,5S]-4-amino-1- [2-(hydroxymethyl)- 1,3-oxathiolan-5-yl]-2(1H)-pyrimidin-2-one (lamivudine) through resolution of racemic lamivudine by cocrystal formation with (S)- BINOL has been demonstrated. Lamivudine of very high pu
- Roy, Bhairab Nath,Singh, Girij Pal,Srivastava, Dhananjai,Jadhav, Harishchandra S.,Saini, Manmeet B.,Aher, Umesh P.
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experimental part
p. 450 - 455
(2010/04/22)
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- METHOD FOR RESOLVING ENANTIOMERS FROM RACEMIC MIXTURE HAVING CHIRAL CARBON IN ALPHA POSITION OF NITROGEN
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Disclosed relates to a simplified method for resolving enantiomers by dissolving a racemic mixture having chiral carbon in α-position of nitrogen and an amino acid to prepare a diastereomeric salt, not using catalyses or enzymes, with enhancing the optical purity remarkably. Moreover, the present invention can prepare the enantiomers in large quantities without using expensive catalysts or without controlling the reaction conditions for the activity of enzymes applied.
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Page/Page column 6
(2009/03/07)
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- METHOD FOR RESOLVING ENANTIOMERS FROM RACEMIC MIXTURE HAVING CHIRAL CARBON IN ALPHA POSITION OF NITROGEN
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Disclosed relates to a simplified method for resolving enantiomers by dissolving a racemic mixture having chiral carbon in α-position of nitrogen and an amino acid to prepare a diastereomeric salt, not using catalyses or enzymes, with enhancing the optical purity remarkably. Moreover, the present invention can prepare the enantiomers in large quantities without using expensive catalysts or without controlling the reaction conditions for the activity of enzymes applied.
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Page/Page column 15-16; 18; 20
(2010/11/28)
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- PROCESS FOR PREPARING SUBSTITUTED 1,3-OXATHIOLANES WITH ANTIVIRAL PROPERTIES
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Disclosed are processes for preparing compounds of formula (I) and pharmaceutically acceptable salts or esters thereof, wherein R2 is a purine or pyrimidine base or an analogue or derivative thereof; and Z is S, S = O or SO2. The invention also relates to
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- 2-Substituted-4-substituted-1,3-dioxolanes and use thereof
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Nucleoside analogues containing a 1,3-dioxolane structure are suitable antiviral agents, particulary for the treatment of the HIV infections in mammals, especially humans. Examples of the nucleoside analogues include: cis-2-acetoxymethyl-4-(thymin-1′-yl)-1,3,-dioxolane, cis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, cis-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane, and cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane. These compounds can be in the form of their racemates or their separate enantiomers.
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Page column 39
(2010/11/29)
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- 1,3-oxathiolane nucleoside analogues
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(?)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, its pharmaceutically acceptable derivatives, pharmaceutical formulation thereof, methods for its preparation and its uses as an antiviral agent are described.
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- Processes for the diastereoselective separation of nucleoside analogue synthetic intermediates
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The present invention relates to highly diastereoselective processes for production of cis-nucleosides and nucleoside analogues and derivatives in high optical purity and intermediates useful in those processes.
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- Processes for the diastereoselective synthesis of nucleoside analogues
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The present invention relates to highly diastereoselective processes for production of cis-nucleosides and nucleoside analogues and derivatives in high optical purity, and intermediates useful in those processes.
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- Enantioselective enzymatic synthesis of the anti-viral agent lamivudine (3TC)
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A novel enzymatic resolution of α-acetoxysulfides has been used as the key step in the synthesis of the important antiviral nucleoside analogue lamivudine. The synthesis proceeds via a configurationally stable hemithioacetal which cyclises in situ to form the required oxathiolane nucleus, which can then be converted into the target nucleoside in 4 steps.
- Milton,Brand,Jones,Rayner
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p. 6961 - 6964
(2007/10/02)
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- Enzymic Resolution of Oxathiolane Intermediates - An Alternative Approach to the Anti-viral Agent Lamivudine (3TCTM)
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A number of commercially available lipases and proteases was screened for the ability to hydrolyse enantioselectively racemic oxathiolane 2.Mucor miehei lipase was identified as the most efficient biocatalyst.Bioconversion of 2 afforded enantiomerrically-
- Cousins, Rick P.C.,Mahmoudian, Mahmoud,Youds, Peter M.
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p. 393 - 396
(2007/10/02)
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- Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
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Disclosed are processes for preparing compounds of the formula (I) and pharmaceutically acceptable salts or esters thereof: STR1 wherein R2 is a purine or pyrimidine base or an analogue or derivative thereof; and Z is S, S=O or SO2.
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- Synthesis of (±)-cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine and its (±)-trans isomer
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The title compounds were synthesized by the formation of 2-[(benzyloxy)methyl]-1,3-oxathiolan-5-one and subsequent DIBALH reduction, acetylation, coupling with N-(1,2-dihydro-2-oxo-4-pyrimidinyl)-2-ethylhexanamide and deprotection.
- Huang,Rideout,Martin
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p. 195 - 207
(2007/10/02)
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- Asymmetric Synthesis and Biological Evaluation of β-L-(2R,5S)- and α-L-(2R,5R)-1,3-Oxathiolane-Pyrimidine and -Purine Nucleosides as Potential Anti-HIV Agents
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In order to study the structure-acivity relationships of L-oxathiolanyl nucleosides as potential anti-HIV agents, a series of enantiomerically pure L-oxathiolanyl pyrimidine and purine nucleosides were synthesized and evaluated for anti-HIV-1 activity in human peripheral blood mononuclear (PBM) cells.The key intermediate 8 was synthesized starting from L-gulose via 1,6-thiaanhydro-L-gulopyranose.The acetate 8 was condensed with thymine, 5-substituted uracils and cytosines, 6-chloropurine, and 6-chloro-2-fluoropurine to give pyrimidine and purine nucleosides.Upon evaluation of these final nucleosides, the 5-fluorocytosine derivative 51 was found to be the most potent compound among those tested.In the case of 5-substituted cytosine analogues, the antiviral potency was found to be in the following decreasing order: cytosine (β-isomer) > 5-iodocytosine (β-isomer) > 5-fluorocytosine (α-isomer) > 5-methylcytosine (α-isomer) > 5-methylcytosine (β-isomer) > 5-bromocytosine (β-isomer) > 5-chlorocytosine (β-isomer).Among the thymine, uracil, and 5-substituted uracil derivatives, thymine (α-isomer) and uracil (β-isomer) derivatives exhibited moderate anti-HIV activity.In the purine series, the antiviral potency is found to be in the following decreasing order: adenine (β-isomer) > 6-chloropurine (β-isomer) > 6-chloropurine (α-isomer) > 2-NH2-6-Cl-purine (β-isomer) > guanine (β-isomer) > N6-methyladenine (α-isomer) > N6-methyladenine (β-isomer).The cytotoxicity was also determined in human PBM cells as well as Vero cells.None of the synthesized nucleosides was toxic up to 100 μ in PBM cells.
- Jeong, Lak S.,Shinazi, Raymond F.,Beach, J. Warren,Kim, Hea O.,Nampalli, Satyanarayana,et al.
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p. 181 - 195
(2007/10/02)
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- Structure-Activity Relationships of β-D-(2S,5R)- and α-D-(2S,5S)-1,3-oxathiolanyl Nucleosides as Potential Anti-HIV Agents
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The β-D-(2S,5R)- and α-D-(2S,5S)-1,3-oxathiolanylpyrimidine and -purine nucleosides with natural nucleoside configuration were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells.The key intermediate 14, which was uti
- Jeong, Lak S.,Schinazi, Raymond F.,Beach, J. Warren,Kim, Hea O.,Shanmuganathan, Kirupathevy,et al.
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p. 2627 - 2638
(2007/10/02)
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- An efficient synthesis of enantiomerically pure (+)-(2S,5R)-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine [(+)-BCH-189] from d-galactose
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An efficient and short synthesis of enantiomerically pure (+)-BCH-189 has been accomplished from D-galactose via 1,6-thioanhydro-D-galactose.
- Jeong, Lak S.,Alves, Antonio J.,Carrigan, Sean W.,Kim, Hea O.,Warren Beach,Chu, Chung K.
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p. 595 - 598
(2007/10/02)
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- Enantiomeric Synthesis of (+)-BCH-189 cytosine> from D-Mannose and Its Anti-HIV Activity
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Enantiomerically pure (+)-BCH-189 has been synthesized from D-mannose via 1,6-thioanhydro-D-mannose and its anti-HIV activity has been determined in peripheral blood mononuclear cells.
- Chu, Chung K.,Beach, J. Warren,Jeong, Lak S.,Choi, Bo G.,Comer, Frank I.,et al.
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p. 6503 - 6505
(2007/10/02)
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