- Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation
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A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials - we refer to this as supply-centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.
- Burns, Justina M.,Gupton, B. Frank,Kashinath, K.,McQuade, D. Tyler,Snead, David R.,Stringham, Rodger W.
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p. 2266 - 2270
(2020/11/23)
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- Large-Scale Stereoselective Synthesis of 1,3-Oxathiolane Nucleoside, Lamivudine, via ZrCl4-Mediated N-Glycosylation
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A stereoselective large-scale synthetic process is described to produce 1,3-oxathiolane nucleoside, lamivudine. A mild, inexpensive, and readily available zirconium (IV) chloride (ZrCl4) catalyst acts as a substrate activator for the key N-glycosylation step at room temperature. An optimum of 0.5 equiv of ZrCl4 is required, which gives encouraging results with respect to chemical efficiency and stereoselectivity. The focus of this work was to develop a new Lewis acid catalyst for N-glycosylation reaction that permits mild and selective synthesis of lamivudine at a large scale. It allowed preferential formation of a single isomer of nucleoside out of four possible stereoisomers, starting from the corresponding 1,3-oxathiolane acetate substrate (racemic and/or diastereomeric mixture of isomers). The thermal behavior for the critical N-glycosylation step was also studied by differential scanning calorimetry and reaction calorimetry techniques.
- Aher, Umesh P.,Jadhav, Harishchandra S.,Jayashree, B. S.,Shenoy, Gautham G.,Singh, Girij P.,Srivastava, Dhananjai
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p. 387 - 397
(2020/04/08)
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- Synthetic method for lamivudine
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The invention provides a synthetic method for lamivudine. The synthetic method comprises the following steps: cheap easily-available dihaloacetic acid is used as a raw material, the dihaloacetic acidand L-menthol are subjected to condensation, hydrolysis is performed to obtain menthyl glyoxylate, the menthyl glyoxylate and 2,5-dihydroxy-1,4-dithiane are subjected to condensation, halogenation isperformed, the halogenated product and silanized cytosine are subjected to coupling, reduction is performed, the reduced product and salicylic acid are subjected to salt formation to obtain the a salicylate, and finally recrystallization is performed to obtain the optically-pure lamivudine. According to the method provided by the invention, the raw materials used in the whole synthetic process arecheap and easy to obtain, the synthetic process is simple, the synthetic conditions are mild, so that the synthetic costs of the lamivudine are greatly reduced; the raw material utilization rate andreaction selectivity are high, so that the yield of the obtained lamivudine is higher; and at the same time, a chiral substrate is easily removed during the synthesis, three waste (waste water, wastegas and solid waste) generated in the method are less, and the method is suitable for industrialized large-scale production of the lamivudine.
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- Semi-continuous multi-step synthesis of lamivudine
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We report the first continuous flow synthesis of lamivudine, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5-acetoxy oxathiolane) was prepared by an integrated two step continuous flow process from l-menthyl glyoxalate hydrate in a single solvent, in 95% overall conversion. For the crucial glycosidation reaction, using pyridinium triflate as the novel catalyst, an improved conversion of 95% was obtained. The overall isolated yield of the desired isomer of lamivudine (40%) was improved in the flow synthesis compared to the batch process.
- Mandala, Devender,Chada, Sravanthi,Watts, Paul
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p. 3444 - 3454
(2017/04/26)
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- PROCESS FOR PRODUCING LAMIVUDINE AND EMTRICITABINE
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This invention provides for flow and batch synthesis processes for the production of Lamivudine and Emtricitabine, including flow and batch synthesis processes wherein at least of the synthesis steps are conducted in a solvent free environment.
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Page/Page column 19; 20; 21; 22
(2018/01/20)
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- Preparation method for nucleoside analogue
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The invention discloses a preparation method for nucleoside analogue. The preparation method comprises a reaction shown in the description, wherein R in the formula is hydrogen or fluorine. The preparation method is characterized in that preparation of a compound in formula III is achieved through chlorination between a compound in formula II and oxalyl chloride. By means of the method, the nucleoside analogue intermediate used for preparing lamivudine or emtricitabine can be prepared, the enantioselectivity is high, the chemical purity can reach 99% or above or even to 99.5% or above, the mol yield can reach 85% or above, and the preparation method has the advantages of being low in toxicity and environmentally friendly and has remarkable value for industrialization of the lamivudine or the emtricitabine.
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Paragraph 0024; 0026; 0027; 0028; 0029; 0030
(2017/01/02)
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- Highly stereoselective synthesis of lamivudine (3TC) and emtricitabine (FTC) by a novel N -glycosidation procedure
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The combined use of silanes (Et3SiH or PMHS) and I2 as novel N-glycosidation reagents for the synthesis of bioactive oxathiolane nucleosides 3TC and FTC is reported. Both systems (working as anhydrous HI sources) were devised to act as substrate activators and N-glycosidation promoters. Excellent results in terms of chemical efficiency and stereoselectivity of the reactions were obtained; surprisingly, the nature of the protective group at the N4 position of (fluoro)cytosine additionally influenced the stereochemical reaction outcome.
- Caso, Maria Federica,Dalonzo, Daniele,Derrico, Stefano,Palumbo, Giovanni,Guaragna, Annalisa
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p. 2626 - 2629
(2015/06/16)
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- A STEREOSELECTIVE PROCESS FOR PREPARATION OF 1,3-OXATHIOLANE NUCLEOSIDES
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The present invention relates to a stereoselective glycosylation for the preparation of 1,3-oxathiolane nucleoside in high yield and high optical purity. The invention specifically relates to a process of the preparation of Lamivudine and Emtricitabine using zirconium (IV) chloride (ZrCl4) as a catalyst in glycosylation.
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Page/Page column 19; 20
(2013/03/26)
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- NOVEL PROCESS FOR THE PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE
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The present invention relates to an improved process for the preparation of cis-nucleoside derivative of formula-1 involving chlorination of the compound of formula-2 followed by reaction with compound of formula-3 in presence of a base to get compound of formula-4, reacting the compound of formula-4 with an alkyl halide (RiX) to get a quaternary ammonium salt then with cytosine derivative of formula-5 to provide the compound of formula-6, optionally de-protecting the compound of formula-6 to the compound of formula-7, reducing compound of formula-7 with metal catalyst in presence of a buffer solution, then adding an organic acid to get the compound of formula-8, and converting the compound of formula-8 to cis-nucleoside derivative of formula-1. The present invention further relates to novel cis-nucleoside derivative of formula-8. The present invention also relates to a pharmaceutical composition comprising cis-nucleoside derivative of formula-1 with excipients.
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Page/Page column 33
(2011/09/14)
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- PROCESS FOR PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE
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The present invention relates to a novel and stereoselective synthetic process for the preparation of optically active cis-nucleoside derivatives of compound of Formula (I), wherein R3 represents H, F, Cl, C1-16 alkyl.
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Page/Page column 9
(2011/11/30)
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- IMPROVED PROCESS FOR NUCLEOSIDES
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The present invention relates to improved process for the preparation of lamivudine or emtricitabine. Thus, (1'R,2'S,5'R)-menthyl- 5(R,S)-acetoxy-[1,3]-oxathiolane-2(R)-carboxylate is reacted with N-propinoyl cytosine in hexamethyl disilazane and then added trityl perchlorate to obtain a solid containing (1'R,2'S,5'R)-menthyl-5S-(N-4''-propionylcytosin-1''-yl)-[1,3]-oxathiolane -2R-carboxylate. The solid obtained above is reacted with methane sulfonic acid to obtain (2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)- [1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl ester. The above compound is reduced with sodium borohydride to obtain lamivudine.
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Page/Page column 12-13
(2011/08/03)
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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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- PROCESS FOR THE PREPARATION OF SUBSTITUTED 1,3-OXATHIOLANES
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The present invention relates to a process for the preparation of substituted 1,3-oxathiolanes. The present invention specifically relates to a process for the preparation of lamivudine.
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Page/Page column 7
(2010/12/29)
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- PROCESS FOR THE PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE
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The present invention relates to a novel and stereoselective synthetic process for the preparation of optically active cis-nucleoside derivatives of compound of Formula (I), wherein R3 represents H, F, Cl, C1-16 alkyl.
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Page/Page column 26
(2010/08/08)
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- PROCESS FOR THE PREPARATION OF SUBSTITUTED 1,3-OXATHIOLANES
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The present invention relates to a process for the preparation of substituted 1,3- oxathiolanes. The present invention specifically relates to a process for the preparation of lamivudine.
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Page/Page column 17
(2009/07/03)
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF SUBSTITUTED 1, 3-OXATHIOLANES, ESPECIALLY LAMIVUDINE
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The present invention relates to process and intermediates for the preparation of substituted 1,3-oxathiolanes. The present invention specifically relates to a process for the preparation of lamivudine.
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Page/Page column 22
(2009/07/03)
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- Practical enantioselective synthesis of lamivudine (3TC) via a dynamic kinetic resolution
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A practical enantioselective synthesis of lamivudine 1 is described. A highly effective dynamic kinetic resolution of the 5-hydroxyoxathiolane, followed by chlorination and introduction of cytosine provides an efficient synthesis of lamivudine.
- Goodyear, Michael D.,Hill, Malcolm L.,West, Jono P.,Whitehead, Andrew J.
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p. 8535 - 8538
(2007/10/03)
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