147027-10-9

Basic information

• Product Name: (1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid
• Synonyms: (2R,5S)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 5-(4-amino-2-oxopyrimidin-1(2H)-yl)-1,3-oxathio;Menthyl-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid;(2R,5S)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 5-(4-amino-2-oxopyrimidin-1(2H)-yl)-1,3-oxat;(1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid;(1R,2S,5R)-MENTHYL-(2R,5S)-5-(4-AMINO-2-OXO-2H-5-FLUORO-PYRIMIDIN-1-YL)-[1,3]-OXATHIOLANE-2-CARBOXYLIC ACID;(1'R,2'S,5'R)-Menthyl-(2R,5S)-5-(4-Amino-2-Oxo-2H-Pyrimidin-1-yl)-[1,3]Oxathiolane-2-Caboxylicacid;(2R-CIS)-5-(4-AMINO-1,2-DIHYDRO-2-OXO-1-PYRIMIDINYL);(2R-CIS)-5-(4-AMINO-1,2-DIHYDRO-2-OXO-1-PYRIMIDINYL) (CME)
• CAS NO: 147027-10-9
• Molecular Formula: C₁₈H₂₇N₃O₄S
• Molecular Weight: 381.48968
• EINECS: 1308068-626-2
• Product Categories: chiral;Chiral Reagents;Heterocycles;Sulfur & Selenium Compounds
• Mol File: 147027-10-9.mol

Chemical Properties

• Melting Point: 203-210°C
• Boiling Point: 524.954 °C at 760 mmHg
• Flash Point: 271.283 °C
• Appearance: tan solid
• Density: 1.421 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.655
• Storage Temp.: -20°C Freezer
• PKA: 4.18±0.10(Predicted)
• CAS DataBase Reference: (1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid(147027-10-9)
• EPA Substance Registry System: (1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid(147027-10-9)

Safety Data

• Hazardous Substances Data: 147027-10-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
(1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid is used as an intermediate in the synthesis of Lamivudine for the treatment of chronic hepatitis B and HIV-1. Its role in the pharmaceutical industry is crucial, as it contributes to the development of life-saving medications for patients suffering from these diseases.
Used in Antiviral Applications:
As a key component in the production of Lamivudine, (1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid plays a significant role in the fight against viral infections. Lamivudine, the final product, is an effective antiviral drug that helps control the replication of the hepatitis B virus and HIV, improving the quality of life for patients and potentially extending their lifespan.
Used in Research and Development:
The compound's unique structure and properties make it an interesting subject for further research and development in the field of medicinal chemistry. Scientists and researchers may explore its potential applications in the development of new drugs or therapies, as well as its interactions with other biological molecules and systems.

InChI:InChI=1/C18H27N3O4S/c1-10(2)12-5-4-11(3)8-13(12)24-16(22)17-25-15(9-26-17)21-7-6-14(19)20-18(21)23/h6-7,10-13,15,17H,4-5,8-9H2,1-3H3,(H2,19,20,23)/t11-,12+,13-,15+,17-/m1/s1

Upstream product

• 147027-09-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-(methylcarbonyloxy)-1,3-oxathiolane-2-carboxylate 
• 202122-17-6 (tert-Butyl-dimethyl-silanyl)-[2-(tert-butyl-dimethyl-silanyloxy)-pyrimidin-4-yl]-amine 
• 18037-10-0 2,4-O,N-bis(trimethylsilyl)cytosine 
• 288325-76-8 5S-chloro-[1,3]oxathiolane-2R-carboxilic acid 2-(1'R,2'S,5'R)-isopropyl-5-methyl-cyclohexyl ester 
• 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 
• 1144099-18-2 (1'R,2'S,5'R)-menthyl-5(R,S)-acetoxy-[1,3]-oxathiolane-2R-carboxylate 
• 1235712-37-4 (2R,5S)-5-(N-4-propionylcytosin-1-yl)-1,3-oxathiolane-2R-carboxylic acid (1'R,2'S,5'R)-menthyl ester 
• 1039400-12-8 (2R,5S)-5-(cytosin-1-yl)-1,3-oxathiolane-2-carboxylic acid (1'R,2'S,5'R)-menthyl ester methanesulfonic acid sakt 
• 71-30-7 Cytosine 
• 111969-64-3 L-menthyl glyoxylate monohydrate 
• 200396-19-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate 
• 2216-51-5 (-)-menthol 
• 21758-30-5 (1R,2S,5R)-(-)-menthyl dichloroacetate 
• 26315-61-7 L-menthyl glyoxylate 

Downstream Products

• 134678-17-4 lamivudine 
• 173522-96-8 lamivudine salicyclic acid salt 
• 1321928-69-1 4-amino-1-((2R,5S)-2-hydroxymethyl-[1,3]oxothiolane-5-yl)-1H-pyrimidin-3-one 2-fluorobenzoic acid salt 
• 2216-51-5 (-)-menthol 

Relevant articles and documents

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.

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.

Synthetic method for lamivudine

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.

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.

PROCESS FOR PRODUCING LAMIVUDINE AND EMTRICITABINE

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.

Preparation method for nucleoside analogue

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.

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.

A STEREOSELECTIVE PROCESS FOR PREPARATION OF 1,3-OXATHIOLANE NUCLEOSIDES

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.

PROCESS FOR PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE

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.

IMPROVED PROCESS FOR NUCLEOSIDES

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.