Purine Derivative Synthesis via Propanediol Heating
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Solution Overview
Problem
Current synthetic methods for preparing CDK inhibitor compound [1] face challenges such as low yields, poor stereoselectivity, and lengthy reaction times, making them unsuitable for scale-up and requiring excessive reagents and side products.
Innovation Solution
A process involving forming a reaction mixture of compound [2], compound [3], and 1,2-propanediol or polyethylene glycol, followed by heating at temperatures above 150°C to produce compound [1], which improves yield and stereoselectivity, and includes steps for converting the compound into a crystalline L-tartrate salt with enhanced purity and efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the coupling reaction is carried out in DIEA and ethylene glycol at 125°C for 48 hours, then the yield of crude compound [1] is improved to 59%, but the overall yield after crystallisation is only 49.4% and the reaction time is lengthy
Solution Approach 1:
The patent changes the reaction temperature parameter from 125°C to 150°C and modifies the solvent system from ethylene glycol to 1,2-propanediol or polyethylene glycol. These parameter changes result in improved reaction efficiency with 79% overall yield and reduced reaction time, resolving the contradiction between productivity and time loss
Solution Approach 2:
The patent employs readily available solvents (1,2-propanediol or polyethylene glycol) that facilitate the reaction under milder conditions, allowing for faster reaction times while maintaining high yields. The simple crystallisation procedure using common solvents like MTBE or ethyl acetate also contributes to time efficiency
2Ease of manufacture
If the MeLi/CuBr.SMe2 reduction step is used to prepare compound [3], then the compound is obtained, but the stereoselectivity is poor with only 75% d.e.
Solution Approach 1:
The patent replaces the MeLi/CuBr.SMe2 reduction system with an alternative reduction method using NaBH4 in isopropanol. This parameter change in the reduction conditions dramatically improves stereoselectivity while maintaining ease of manufacture, as the new conditions are simpler and more selective
3Productivity
If the coupling reaction conditions from WO 2011/089401 are used, then the crude yield is improved to 59%, but excessive reagents are required and side products are formed
Solution Approach 1:
The patent optimizes the coupling reaction parameters by using 1,2-propanediol or polyethylene glycol as solvent at 150°C, which improves the crude yield to 79% while minimizing side product formation. The optimized conditions reduce reagent excess requirements and improve overall reaction efficiency
Solution Approach 2:
The patent uses 1,2-propanediol or polyethylene glycol as an intermediary solvent that facilitates the coupling reaction between compound [2] and compound 3, enabling high yields with minimal side products. The solvent acts as a mediator that promotes selective reaction
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 a higher overall yield of 79% for the crystalline free base and 87% for the L-tartrate salt, with improved purity and reduced reaction time, making it more suitable for scale-up and economic production.
Implementation Method 1
heating said reaction mixture to a temperature of at least 150°C to form a compound of formula 1
Data Source
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AI summary
The present invention relates to a process for preparing a compound of formula [I], said process comprising the steps of: formula [II]+formula [III]−>formula [I] (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof, and optionally (d) a base; (ii) heating said reaction mixture to a temperature of at least about 150°C to form a compound of formula [I]; (iii) isolating said compound of formula [I]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (A) where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I].