2,3,5-Tri-O-benzyl-D-ribonolactone: Importance in Pharmaceutical Chemistry and its Preparation Method

General Description

2,3,5-Tri-O-benzyl-D-ribonolactone, with a molecular formula of C26H26O5, plays a crucial role in pharmaceutical chemistry. It acts as an intermediate in synthesizing remdesivir, an antiviral medication effective against RNA viruses like SARS-CoV-2. The preparation method involves specific steps, including dissolution in DMSO, reaction with Ac2O, and purification through column chromatography. An alternative method using a continuous flow microchannel reactor offers advantages such as shorter reaction times and high purity. Overall, 2,3,5-Tri-O-benzyl-D-ribonolactone's unique chemical profile and significance in drug development make it valuable in pharmaceutical synthesis and antiviral medication production.

Figure 1. 2,3,5-Tri-O-benzyl-D-ribonolactone

Chemical Characteristics

2,3,5-Tri-O-benzyl-D-ribonolactone is a chemical compound known for its distinctive molecular structure and significant role in pharmaceutical chemistry. Identified by its CAS Number 55094-52-5, it has a molecular formula of C26H26O5, indicating its composition of carbon, hydrogen, and oxygen atoms. With a molecular weight of approximately 429.684, it demonstrates considerable size and complexity. Its physical properties, including predicted melting and boiling points, as well as density, influence its chemical behavior. Notably, 2,3,5-Tri-O-benzyl-D-ribonolactone acts as an intermediate in synthesizing certain pharmaceuticals, underscoring its importance in medicinal chemistry. Its unique chemical characteristics render it valuable across various applications, owing to its role as a versatile building block in drug development. In essence, 2,3,5-Tri-O-benzyl-D-ribonolactone's distinct chemical profile grants it specific properties that are instrumental in pharmaceutical synthesis and other related fields. ¹

Importance in Pharmaceutical Chemistry

2,3,5-Tri-O-benzyl-D-ribonolactone holds significant importance in pharmaceutical chemistry, particularly in the synthesis of remdesivir, an antiviral medication. 2,3,5-Tri-O-benzyl-D-ribonolactone serves as a crucial intermediate in the synthesis of remdesivir, which has gained attention due to its potential efficacy against various RNA viruses, including coronaviruses such as SARS-CoV-2, the virus responsible for COVID-19. In the synthesis process, (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one reacts with 4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine via an addition reaction. This step is crucial in forming the core structure necessary for further modification into remdesivir. The subsequent steps involve cyanation, debenzylation, heterocyclization, and amination. These reactions facilitate the transformation of the intermediate compound into remdesivir, a broad-spectrum antiviral medication with potential applications in treating various viral infections, including Ebola, Marburg, SARS, MERS, and COVID-19. Due to its role as an intermediate in the synthesis of remdesivir, 2,3,5-Tri-O-benzyl-D-ribonolactone plays a vital role in the pharmaceutical industry, contributing to the development of therapeutic agents targeting RNA viruses and potentially aiding in the management of viral outbreaks and pandemics. ²

Preparation Method

The method for preparing 2,3,5-Tri-O-benzyl-D-ribonolactone involves a series of steps carried out under specific conditions to achieve a high yield and purity of the desired product. Initially, 2,3,5-Tri-O-benzyl-D-ribonolactone is dissolved in dimethyl sulfoxide (DMSO), followed by the addition of acetic anhydride (Ac2O) to the reaction mixture. This solution is stirred overnight at room temperature to facilitate the reaction. After completion of the reaction, the mixture is poured into ice water and stirred, allowing the product to precipitate. The reaction mixture is then extracted with ethyl acetate (EtOAc) to isolate the organic layer. Washing with water and brine removes impurities, and drying over sodium sulfate removes any remaining water. The concentrated mixture is then purified using flash column chromatography with a solvent gradient of 10% to 25% ethyl acetate/petroleum ether. This process separates impurities from the desired product, yielding 2,3,5-Tri-O-benzyl-D-ribonolactone with a high degree of purity. Additionally, a transformation step is mentioned, involving the formation of cyclic ethers. However, the primary focus of the method is on the oxidation reaction to obtain the desired lactone product. An alternative method is also proposed, involving the oxidation of 2,3,5-Tri-O-benzyl-D-ribonolactone with sodium hypochlorite in a continuous flow microchannel reactor. This method addresses issues such as long reaction times, high reaction conditions, and high costs associated with traditional methods. It offers advantages such as simplicity, safety, shorter reaction times, high conversion rates, and high purity of the product, making it suitable for industrial-scale production. ³

Reference

1. Chemical Safety Data Sheet: 2,3,5-Tri-O-benzyl-D-ribonolactone. 2023; CBnumber: CB51180311.

2. Yang YQ, Tong GQ, Liu CR, Feng B, Wang F. Preparation of remdesivir intermediate. 2023; Patent Number: CN115703796.

3. Chen BS, Ye JX, Li DW. Method for preparing 2,3,5-tribenzyloxy-D-ribono-1,4-lactone by oxidation in continuous flow microchannel reactor. 2022; Patent Number: CN111548328.

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