Synthetic options towards the manufacture of (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl} - 1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(metheno)pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing synthesis processes for the macrocycle compound (6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(metheno)pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one are not scalable due to high costs of Grubbs (II) reagents and low yields, necessitating a more economical and efficient process for larger quantities.
Innovation Solution
A method involving specific reactions and intermediates, including the use of compounds 1 and 2, ester hydrolysis, chiral auxiliary activation, and enzymatic reduction, coupled with metal catalysts and coupling agents, to synthesize the compound in a scalable manner.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the disclosed multistep synthesis process using Grubbs (II) reagent is used, then the macrocycle compound can be prepared, but the production cost is high and the process is not suitable for commercial scale
Solution Approach 1:
The patent replaces the expensive Grubbs (II) reagent with a cheaper alternative catalyst system that can be used for commercial-scale synthesis. The new process employs readily available catalysts and reagents that reduce production costs while maintaining synthesis effectiveness, making the process economically viable for manufacturing.
Solution Approach 2:
The patent modifies reaction parameters including temperature, solvent systems, and catalyst loading to optimize the synthesis process for scale-up. By adjusting these parameters, the process achieves higher yields and improved manufacturability without requiring the expensive Grubbs (II) reagent.
2Productivity
If the disclosed synthesis process is used, then the macrocycle compound can be prepared, but the yield is low
Solution Approach 1:
The patent introduces preliminary protection group strategies and pre-activation steps that prevent side reactions and improve the efficiency of key transformation steps. By preparing intermediates in advance with appropriate protecting groups, the overall yield is improved and material loss is reduced.
Solution Approach 2:
The patent employs intermediate compounds and protecting groups that facilitate the synthesis by preventing decomposition and side reactions. These intermediaries allow for better control of reaction pathways, leading to improved yields and reduced material loss throughout the multistep synthesis.
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 new process achieves higher yields and reduces production costs, making it suitable for commercial-scale synthesis of the macrocycle compound.
Implementation Method 1
a transaminase enzyme in the presence of an amine source, different recycling systems, and a co-factor to generate the amine stereogenic center
Implementation Method 2
12b) a transaminase enzyme in the presence of an amine source, different recycling systems, and a co-factor to generate the amine stereogenic center
Implementation Method 3
reducing the nitro group in Compound 9 to Compound 10
Implementation Method 4
subsequently reacting Compound 7 in the presence of a metal catalyst with Compound 8
Data Source
AI summary
Highly efficient methods are provided for preparing key intermediates in the synthesis of Compound (I), which are broadly applicable and can provide selected components having a variety of substituents groups.