2′-O-substituted Purine Nucleoside Synthesis via Ring Opening
Solution Overview
Problem
Current methods for synthesizing 2′-O-substituted purine nucleosides are inefficient, expensive, and produce multiple impurities due to the use of corrosive reagents and enzymes, as well as unstable alkyl bromides, leading to low yields and difficulties in separation.
Innovation Solution
The process involves treating 8,2′-cyclopurine nucleosides with a Lewis acid ester and a weak base to open an anhydro or thioanhydro linkage, followed by reduction, which eliminates the need for expensive enzymes and reduces impurities by avoiding alkylation with alkyl bromides, using a borane-chelated alkyl group for ring opening.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the conventional method using corrosive triflic acid and heating at 150°C under pressure is used, then the conversion of purine to 2,6-diaminopurine riboside is achieved, but the process requires several days of heating and produces low yield
Solution Approach 1:
The patent changes the reaction parameters by using a different chemical approach (deamination of 2,6-diaminopurine riboside) that operates under milder conditions (room temperature or moderate heating) compared to the conventional high-temperature pressurized method, thereby reducing reaction time and improving efficiency
Solution Approach 2:
The patent replaces the mechanical/physical method of high-temperature and high-pressure heating with a chemical method using adenosine deaminase enzyme or chemical deamination reagents, which achieves the same transformation under more benign conditions with shorter reaction times
2Productivity
If alkylation with methoxyethyl bromide is performed, then 2′-O-methoxyethyl-2,6-diaminopurine riboside is formed, but a mixture of various substituted alkylated products is produced including mono-substituted, 3′-O-methoxyethyl, and di-substituted products
Solution Approach 1:
The patent removes the problematic alkylation step that generates multiple substituted products and instead uses a selective deamination approach that directly converts 2,6-diaminopurine riboside to the desired 2′-O-methoxyethyl product without forming unwanted mono-substituted, 3′-O-substituted, or di-substituted byproducts
Solution Approach 2:
Instead of building the 2′-O-methoxyethyl group through alkylation (adding to the molecule), the patent uses deamination (removing a functional group) to achieve the same structural transformation, thereby avoiding the formation of multiple alkylated isomers
3Ease of manufacture
If methoxyethyl bromide is used for alkylation, then the alkylation reaction proceeds, but the CH3—O bond is easily cleaved with traces of HBr to generate methyl bromide, which leads to a more reactive electrophile and forms 2′-O-methoxyl-2,6-diaminopurine riboside that is very difficult to separate
Solution Approach 1:
The patent eliminates the use of methoxyethyl bromide and HBr that cause bond cleavage and formation of difficult-to-separate byproducts, replacing them with a deamination method using adenosine deaminase or alternative reagents that proceed without generating these problematic side reactions
Solution Approach 2:
The patent introduces adenosine deaminase enzyme or alternative deamination reagents as intermediaries that facilitate the conversion of 2,6-diaminopurine riboside to the desired product through a different mechanistic pathway, avoiding the formation of methyl bromide and the associated separation difficulties
4Productivity
If the conversion of 2′-O-methoxyl-2,6-diaminopurine riboside is performed using adenosine deaminase enzyme, then the desired 2′-O-methoxyethyl purine is obtained, but the overall yield is unattractive due to the expense of the enzyme and low intermediate yield
Solution Approach 1:
The patent seeks to replace the expensive adenosine deaminase enzyme with cheaper chemical deamination reagents or methods that can achieve the same transformation, thereby reducing process cost while maintaining or improving overall yield
Solution Approach 2:
The patent optimizes the synthesis pathway by performing preliminary protection and deprotection steps that ensure high yield of the 2,6-diaminopurine riboside intermediate, which then feeds into the deamination step, thereby improving the overall yield from starting materials to final product
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This method provides a more efficient and cost-effective synthesis of 2′-O-substituted purine nucleosides with fewer impurities, suitable for both small and large-scale production, and eliminates the need for expensive enzymes and unstable alkyl bromides, resulting in improved yields and purity.
Implementation Method 1
treating said 8,2′-cyclopurine nucleoside with a reagent that provides an alkoxy radical capable of opening said anhydro linkage
Implementation Method 2
using a borane-chelated alkyl group for ring opening
Implementation Method 3
followed by reduction, which eliminates the need for expensive enzymes
Data Source
AI summary
The present invention provides an improved process for the synthesis of 2′-O-substituted purine nucleosides. The process includes anhydro or thioanhydro ring opening of a selected 8,2′-cyclopurine nucleoside with a weak nucleophile in the presence of a Lewis acid ester, followed by reduction to afford the desired 2′-O-substituted purine nucleoside.