200396-19-6

Upstream product

• 2216-51-5 (-)-menthol 
• 74441-18-2 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-mercaptoacetate 
• 40018-26-6 1,4-dithiane-2,5-diol 
• 111969-64-3 L-menthyl glyoxylate monohydrate 

Downstream Products

• 1346921-53-6 L-menthyl 5-cytosin-1-yl-1,3-oxathiolane-2-carboxylate 
• 1346921-70-7 C₁₄H₂₃ClO₃S 
• 147027-10-9 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5S)-5-(4-amino-2-oxo-1,2-dihydro-1-pyrimidinyl)-1,3-oxathiolane-2-carboxylate 
• 147126-67-8 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-acetoxy-1,3-oxathiolane-2-carboxylate 
• 147126-65-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5S)-5-(methylcarbonyloxy)-1,3-oxathiolane-2-carboxylate 
• 147126-67-8 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S,5R)-5-(methylcarbonyloxy)-1,3-oxathiolane-2-carboxylate 
• 147027-09-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-(methylcarbonyloxy)-1,3-oxathiolane-2-carboxylate 
• 147126-67-8 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S,5S)-5-(methylcarbonyloxy)-1,3-oxathiolane-2-carboxylate 
• 764659-72-5 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5S)-5-(4-amino-5-fluoro-2-oxo-1,2-dihydro-1-pyrimidinyl)-1,3-oxathiolane-2-carboxylate 
• 147126-78-1 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5S)-5-[4-(methylcarboxamido)-2-oxo-1,2-dihydro-1-pyrimidinyl]-1,3-oxathiolane-2-carboxylate 
• 147126-73-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-(4-amino-2-oxo-1,2-dihydro-1-pyrimidinyl)-1,3-oxathiolane-2-carboxylate 

Relevant academic research and scientific papers

Large-Scale Stereoselective Synthesis of 1,3-Oxathiolane Nucleoside, Lamivudine, via ZrCl4-Mediated N-Glycosylation

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

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.

Semi-continuous multi-step synthesis of lamivudine

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.

Highly stereoselective synthesis of lamivudine (3TC) and emtricitabine (FTC) by a novel N -glycosidation procedure

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.

AN IMPROVED PROCESS FOR THE MANUFACTURE OF LAMIVUDINE

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.