Eribulin Intermediate Synthesis via D-2-deoxyribose Chiral Pool
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Solution Overview
Problem
The existing synthetic methods for eribulin are lengthy, challenging in terms of stereo-control, and complicated in purification due to the presence of numerous chiral carbon atoms, leading to issues with optical purity and stereoselectivity.
Innovation Solution
A novel synthesis method using D-2-deoxyribose as a starting material, involving multi-step reactions such as oxidation, hydroxyl protection, and ring opening, to produce a compound with 99.9% optical purity, simplifying the purification process and improving stereoselectivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing total synthesis routes are used for eribulin, then the synthesis can be completed, but the synthesis route becomes too lengthy (62 steps) and stereo-control becomes extremely difficult
Solution Approach 1:
The patent uses chiral pool strategy by selecting D-2-deoxyribose as starting material, which already contains predetermined chiral centers. This preliminary chiral configuration is maintained throughout the synthesis, avoiding the need for complex stereo-control measures in later steps and significantly reducing the number of synthesis steps required
Solution Approach 2:
The patent changes the starting material parameter from conventional achiral or racemic compounds to a specifically chiral natural product (D-2-deoxyribose). This parameter change fundamentally simplifies the synthesis route by eliminating the need for multiple chiral resolution steps and stereo-selective reactions
2Manufacturing precision
If conventional synthesis methods are used, then intermediates can be produced, but optical purity becomes difficult to control and purification becomes complicated and costly
Solution Approach 1:
The patent employs self-service principle by designing a synthesis route where the chiral information from D-2-deoxyribose automatically directs the stereochemistry of subsequent reactions. The molecular structure itself serves the function of stereo-control, eliminating the need for external chiral auxiliaries or complex purification processes to maintain optical purity
Solution Approach 2:
The patent discards conventional approaches that require extensive chiral resolution and purification steps. By starting with enantiomerically pure D-2-deoxyribose, the method recovers time and resources by eliminating multiple purification steps that would otherwise be necessary to achieve high optical purity
3Manufacturing precision
If synthesis methods with numerous chiral carbon atoms are used, then eribulin structure can be achieved, but stereoselectivity becomes poor and isomers are easily formed that are difficult to remove
Solution Approach 1:
The patent pre-establishes the correct stereochemical configuration by selecting D-2-deoxyribose as the starting material. The chiral centers already present in the starting material guide the formation of subsequent chiral centers through diastereoselective reactions, preventing the formation of incorrect isomers rather than requiring their removal later
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 ensures high optical purity and reduces the complexity of purification, achieving efficient synthesis of eribulin intermediates with minimal impurities, thus meeting the control guidance principles for APIs and lowering purification costs.
Implementation Method 1
carrying out multi-step reactions including oxidation, hydroxyl protection, reduction ring opening, hydroxyl protection removal
Implementation Method 2
carrying out multi-step reactions including oxidation, hydroxyl protection, reduction ring opening, hydroxyl protection removal
Implementation Method 3
carrying out multi-step reactions including oxidation, hydroxyl protection, reduction ring opening, hydroxyl protection removal
Data Source
Figure 1~2
AI summary
The present invention relates to the field of drug synthesis, and particularly relates to an intermediate of eribulin and a synthesis method and use thereof. The present invention provides an intermediate useful for the synthesis of halichondrin B, eribulin or an analog thereof, particularly a structural fragment C27-C35 thereof, and a preparation method and use thereof. The starting materials of the synthetic route disclosed herein are cheap and easy to obtain, and the optical purity of the starting materials can be ensured, so that the optical purity of the structural fragment C27-C35 in halichondrin B, eribulin or the analog thereof is ensured; steps for constructing a chiral center of the structural fragment C27-C35 feature higher diastereoselectivity and yield, in particular preparation methods of compounds of formulae (X), (XI), (XVI) and (XV); by-products of partial reactions can be removed only by recrystallization, which results in easy purification and significant reduce in cost.