Alternative process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1h-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The existing synthetic approaches for preparing compounds of formula (I) are not suitable for commercial production due to low yield, expensive starting materials, cumbersome stereochemical separation and purification, and the lack of robustness in the Swern oxidation step, making them inefficient and costly.
Innovation Solution
A novel process with reduced steps, lower waste generation, and improved cost-effectiveness is developed, involving specific reaction conditions and reagents such as 1,1'-carbonyldiimidazole instead of phosgene, and the use of (R)-(−)-3,3′-Bis(triphenylsilyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate as a catalyst, which simplifies the synthesis and increases yield and stereochemical purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the existing synthetic approach (WO 2015/132276) is used, then the compound can be prepared, but the overall yield is low and the process is expensive
Solution Approach 1:
The patent changes the chemical parameters by replacing phosgene with 1,1'-carbonyldiimidazole as a safer and more efficient reagent. This substitution improves the reaction efficiency and overall yield while reducing the cost and complexity of the synthetic process, directly addressing the low productivity and high cost issues of the existing approach
Solution Approach 2:
The patent employs readily available and inexpensive starting materials such as 3-amino-2,2-dimethylpropanoate hydrochloride and ethyl (R)-3-phenyl-2-oxo-4-propionamino-1-butanone hydrochloride, replacing expensive specialized reagents. This strategy reduces the quantity of substance cost while maintaining high productivity through efficient reaction pathways
2Productivity
If the existing synthetic approach is used, then the compound can be prepared, but cumbersome stereochemical separation and purification is required
Solution Approach 1:
The patent employs chiral pool strategy by selecting starting materials that already possess the required stereochemistry (L-valine derivative and L-leucine derivative). The synthesis process maintains and transfers this chirality through the reaction sequence without requiring additional separation steps, allowing the process to self-service the stereochemical requirement and dramatically simplifying the overall synthesis
Solution Approach 2:
The patent performs preliminary stereochemical selection by choosing chiral starting materials with the correct configuration before the synthesis begins. This preliminary action of selecting enantiomerically pure starting materials prevents the formation of unwanted stereoisomers, eliminating the need for cumbersome separation and purification steps later in the process
3Reliability
If the Swern oxidation step is used, then oxidation can be achieved, but the step lacks robustness
Solution Approach 1:
The patent replaces the complex and non-robust Swern oxidation reagents (oxalyl chloride, DMSO, TEA at low temperatures) with a simpler, more robust oxidation system using sodium chlorite and 2-methyl-2-butene in aqueous acetonitrile at room temperature. This substitution with readily available reagents improves reliability while maintaining ease of manufacture through simpler operational conditions
Solution Approach 2:
The patent changes the oxidation parameters from low-temperature Swern conditions to room temperature sodium chlorite oxidation. This parameter change improves the robustness and reliability of the oxidation step by eliminating the need for strict temperature control and anhydrous conditions, while maintaining ease of manufacture through more forgiving reaction conditions
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 product yield, reduces waste, and lowers costs by simplifying the synthesis and eliminating the need for toxic phosgene reagents, making it more viable for industrial-scale production.
Implementation Method 1
step a) the formation of compound (III), wherein R3 is —CxH2x—; x is 1, 2, 3, 4, 5, 6 or 7;
Implementation Method 2
The suitable reagent is selected from phosgene, diphosgene and triphosgene.
Implementation Method 3
step e) and f) the formation of the compound of formula (IX) via hydrolysis of the compound of formula (VIII),
Data Source
AI summary
The present invention relates to an alternative process for synthesizing a compound of formula (I), R1 is phenyl, which is unsubstituted or substituted with one, two or three substituents independently selected from halogen and C1-6alkyl; R2 is C1-6alkyl; R3 is —CxH2—; x is 1, 2, 3, 4, 5, 6 or 7; or pharmaceutically acceptable salt or diastereomer thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.