134678-17-4Relevant articles and documents
The chemical resolution of racemic CIS-2-hydroxymethyl-5-(Cytosine-1′-YL)-1,3-oxathiolane (BCH-189) - One direct method to obtain lamivudine as anti-HIV and anti-HBV agent
Li, Ji-zhen,Gao, Lian-xun,Ding, Meng-xian
, p. 2355 - 2359 (2002)
Racemic cis-BCH-189 can be resolved to (-)-enantiomer (lamivudine) and (+)-enantiomer by esterification of cis-2-hydroxymethyl-5-(N′4-acetylcyto sine-1′-yl)-1,3-oxathiolane and (+)-menthyl chloroformate in CH3CN with pyridine as base. The two diastereomers of ester were seperated by recrystallization in methanol at 0°C. Lamivudine was obtained by deprotection of (-)-diastereomer with high yield.
Semi-continuous multi-step synthesis of lamivudine
Mandala, Devender,Chada, Sravanthi,Watts, Paul
, p. 3444 - 3454 (2017)
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.
An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly
Abdiaj, Irini,Ahmad, Saeed,Burns, Justina M.,Gopalsamuthiram, Vijayagopal,Gupton, B. Frank,Krack, Rudy,McQuade, D. Tyler,Nelson, Ryan C.,Snead, David R.,Stringham, Rodger W.
, p. 1194 - 1198 (2020)
An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate's anomeric center for N-glycosylation and transferring stereochemical information to the substrate simultaneously. Both enantiomers of the lactic acid derivative are available, and either β-enantiomer in this challenging class of 2′-deoxynucleoside active pharmaceutical ingredients can be formed.
Large-Scale Stereoselective Synthesis of 1,3-Oxathiolane Nucleoside, Lamivudine, via ZrCl4-Mediated N-Glycosylation
Aher, Umesh P.,Jadhav, Harishchandra S.,Jayashree, B. S.,Shenoy, Gautham G.,Singh, Girij P.,Srivastava, Dhananjai
, p. 387 - 397 (2020)
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.
Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation
Burns, Justina M.,Gupton, B. Frank,Kashinath, K.,McQuade, D. Tyler,Snead, David R.,Stringham, Rodger W.
, p. 2266 - 2270 (2020)
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.
Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane-Sodium Iodide-Promoted Vorbrüggen Glycosylation
Mear, Sarah Jane,Nguyen, Long V.,Rochford, Ashley J.,Jamison, Timothy F.
, p. 2887 - 2897 (2022/02/07)
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)
Nucleoside analogs of lamivudine preparation method (by machine translation)
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Paragraph 0039; 0040; 0044; 0045, (2019/07/11)
The invention relates to a method for the preparation of nucleoside analogs lamivudine. Specific, comprises the following steps: methanol in the solvent, a compound of formula III with a reducing agent, after treatment then outputs II compound, further purification, free, formula I compounds. This method is simple in operation, the resulting high product yield, purity as high as 99.5%. The method of post-processing process is simple, solvent is recycled for future use, in accordance with the needs of industrial production. (by machine translation)
Asymmetric synthesis method of lamivudine
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Paragraph 0027; 0028; 0034; 0035; 0036, (2019/11/29)
The invention provides an asymmetric synthesis method of lamivudine. The synthesis method comprises: carrying out condensation on L-menthyl chloroformate used as a starting raw material and geminal dihaloethanol, hydrolyzing to obtain an acetaldehyde alcohol optically-active ester, carrying out condensation with 5,5-dihydroxy-1,4-dithiane to obtain trans 5-hydroxy-1,3-oxathiolane-2-methyl optically-active ester, acetylating, coupling with silanized cytosine, and finally removing the chiral auxiliary agent to obtain the product lamivudine. According to the present invention, the raw materials used in the entire synthesis process are cheap and readily available, and have high utilization rate, such that the synthesis cost of lamivudine is substantially reduced; the synthesis process is simple, the synthesis conditions are mild, the yield of the obtained lamivudine is high, the chiral substrate is easily removed during the synthesis, and the generated three-waste pollutants are less; andthe method is suitable for industrial large-scale production of lamivudine.
A preparation method of lamivudine
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Paragraph 0042; 0064; 0065, (2019/04/02)
The invention discloses a method for preparation of lamivudine. Refined pure 5 S - (cytosine base - 1 ') - 1, 3 - oxathiolane - 2 - ethoxy carbonyl - (1' R, 2'S, 3' R) - menthyl ester; in the weak base and the solvent removed under the condition of chiral L - menthol to get a product of lamivudine. The material of the invention is cheap, the reagents used in the environmental protection, steps is relatively short, mild reaction conditions, atom utilization rate high, high yield, high chemical purity of the obtained product, reach the medical standard, suitable for large-scale production of lamivudine preparation method.
Multienzymatic cascade synthesis of an enantiopure (2R,5R)-1,3-oxathiolane anti-HIV agent precursor
Ren, Yansong,Hu, Lei,Ramstr?m, Olof
, p. 52 - 56 (2019/02/24)
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.
