Islatravir Synthesis via Segmented 8-Step Route
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for preparing islatravir have long processes and low yields, making them difficult to industrialize, and require hard-to-purchase raw materials and dangerous reagents.
Innovation Solution
A method involving 8 steps using 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose as a raw material, including selective hydroxyl protection, oxidation, alkynyl group construction, protecting group conversion, glycosylation, deprotection, and debenzylation reactions, to produce islatravir with a high yield and safer reagents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing synthetic routes are used, then islatravir can be produced, but the process is long and yield is low
Solution Approach 1:
The synthesis process is divided into 8 distinct reaction steps with clear intermediates (Formula II through Formula IX), allowing for systematic optimization and quality control at each stage while maintaining overall process efficiency
Solution Approach 2:
The method performs protective group installation and strategic bond formation in advance (e.g., benzyl protection at C3' and isopropylidene protection at C1'-C2' in starting material), enabling smoother progression through subsequent reaction steps and higher overall yield
2Ease of manufacture
If existing synthetic routes are used, then islatravir can be produced, but the raw materials are hard to purchase
Solution Approach 1:
The method uses commercially available, stable sugar derivatives (ribofuranose-based compounds) as starting materials that can be easily procured from standard chemical suppliers, replacing specialized or expensive ligands required by previous methods
Solution Approach 2:
The synthesis employs standard protecting groups (benzyl, isopropylidene, acetyl) and common reagents (sodium hydride, Dess-Martin periodinane, dimethyl diazomethylphosphonate) that have well-established handling procedures and are readily available, making the process suitable for industrialization
3Reliability
If existing synthetic routes are used, then islatravir can be produced, but dangerous reagents are required
Solution Approach 1:
The method replaces highly reactive and dangerous reagents (such as butyllithium) with safer alternatives that achieve the same chemical transformations (e.g., using dimethyl diazomethylphosphonate for alkynyl group construction), maintaining synthesis capability while improving safety
Solution Approach 2:
The synthesis uses stable intermediate compounds (Formula III through Formula IX) with appropriate protecting groups that facilitate safe handling and storage, allowing reactions to proceed under milder and safer conditions while maintaining product quality
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
The method achieves a high overall yield of 48.6% with easily purchasable and cost-effective starting materials, avoiding dangerous reagents and simplifying the process for industrialization.
Implementation Method 1
subjecting a compound of Formula II as a raw material to selective hydroxyl protection reaction to obtain a compound of Formula III
Implementation Method 2
subjecting the compound of Formula III to hydroxyl oxidation reaction to obtain a compound of Formula IV
Implementation Method 3
subjecting the compound of Formula IV and dimethyl diazomethylphosphonate to reaction under an alkaline condition to obtain a compound of Formula V, such that a terminal alkynyl group of the islatravir is constructed
Implementation Method 4
subjecting the compound of Formula V to protecting group conversion reaction, such that protection by one propylidene group is converted to protection by two acetyl groups to obtain a compound of Formula VI
Implementation Method 5
subjecting the compound of Formula VI to glycosylation reaction, such that a glycosidic bond is constructed to obtain a compound of Formula VII
Implementation Method 6
subjecting the compound of Formula VII to selective deprotection reaction to remove the acetyl groups to obtain a compound of Formula VIII
Implementation Method 7
subjecting the compound of Formula VIII to deoxidation reaction to remove a hydroxyl group at a 2'-position to obtain a compound of Formula IX
Implementation Method 8
subjecting the compound of Formula IX to debenzylation reaction to remove two benzyl groups to produce the islatravir
Data Source
AI summary
Provided is a method for preparing islatravir, including: 1) subjecting compound of Formula II as a raw material to selective hydroxyl protection reaction to obtain compound of Formula III, 2) subjecting the compound of Formula III to hydroxyl oxidation reaction to obtain compound of Formula IV; 3) subjecting the compound of Formula IV and dimethyl diazomethylphosphonate to reaction under an alkaline condition to obtain compound of Formula V; 4) subjecting the compound of Formula V to protecting group conversion reaction to obtain compound of Formula VI; 5) subjecting the compound of Formula VI to glycosylation reaction to obtain compound of Formula VII; 6) subjecting the compound of Formula VII to selective deprotection reaction to obtain compound of Formula VIII; 7) subjecting the compound of Formula VIII to deoxidation reaction to obtain compound of Formula IX; and 8) subjecting the compound of Formula IX to debenzylation reaction to obtain the islatravir.