Thienopyrimidine Derivative Crystallization for High-Purity Synthesis
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Solution Overview
Problem
There is a need for a safe and efficient production method of thienopyrimidine derivatives with gonadotropin releasing hormone antagonistic action, particularly in high yield and high purity.
Innovation Solution
A production method involving specific reactions and conditions, including the use of 1,1′-carbonyldiimidazole and methoxyamine, along with controlled amounts and solvents, to synthesize 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea or its salts, followed by crystallization to obtain high-quality crystals.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional production methods are used for thienopyrimidine derivatives, then the production process is simpler, but the yield and purity are insufficient
Solution Approach 1:
The production process is divided into multiple discrete steps: (1) condensation of thieno[2,3-d]pyrimidine-2,4-dione with 4-aminophenyl group to form intermediate compound, (2) cyclization with pyridazin-3-yl group, (3) reduction of nitro group to amino group, and (4) coupling with carbonyldiimidazole and methoxyamine. Each step has specific reagents, conditions, and purification methods defined, allowing systematic control of purity while managing overall process complexity through modularization.
Solution Approach 2:
The patent employs preliminary actions by using protected intermediates and pre-formed building blocks. For example, the thieno[2,3-d]pyrimidine-2,4-dione is first formed with specific substituents before final coupling, and the nitro group is reduced to amino group in a controlled intermediate step. This allows purification and quality control at each stage, ensuring high final purity while managing complexity through staged synthesis.
2Productivity
If conventional production methods are used for thienopyrimidine derivatives, then the production process is simpler, but the yield is insufficient
Solution Approach 1:
The patent optimizes reaction parameters at each step to maximize yield. Specific conditions include: using 1,1′-carbonyldiimidazole in controlled equivalents (1.05-1.5 eq), controlling pH during hydrolysis (using 2M HCl or NaOH), selecting specific solvents (DMF, DMSO, acetonitrile), and optimizing temperatures (0-100°C range). These parameter optimizations ensure high yield while maintaining manageable process complexity through standardized conditions.
Solution Approach 2:
The synthesis pathway maintains continuous useful action by designing each step to proceed efficiently with minimal idle time. Intermediates are carried forward through controlled purification steps, and reaction conditions are optimized to minimize waste. The multi-step sequence ensures continuous progression from starting materials to final product with high overall yield, while complexity is managed through systematic process integration.
3Reliability
If high quality and high yield are pursued, then the production method becomes safer and more reliable, but the process complexity increases
Solution Approach 1:
The patent incorporates feedback mechanisms through controlled purification steps and quality control at each stage. HPLC analysis is performed to monitor purity, and intermediate compounds are purified by recrystallization or chromatography as needed. This feedback allows real-time adjustment of conditions to ensure safety and reliability, while the systematic approach manages complexity through standardized quality control protocols.
Solution Approach 2:
The patent employs beforehand cushioning by using protected intermediates and controlled reaction conditions that prevent formation of harmful byproducts. Specific measures include: controlling stoichiometry of reagents (using 1.05-1.5 equivalents of carbonyldiimidazole), pH control during hydrolysis (using controlled amounts of HCl or NaOH), and selecting solvents with appropriate boiling points and viscosities. These preventive measures ensure safe production while managing complexity through pre-established control parameters.
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 enables the safe production of high-quality thienopyrimidine derivatives in high yield, suitable for use as raw materials, with reduced impurities and improved purity through controlled reaction conditions and crystallization processes.
Implementation Method 1
reacting 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl) thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione or salt thereof, 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof
Implementation Method 2
adding tetrahydrofuran to the resulting reaction mixture (may be a reaction solution) or 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea or a salt thereof isolated from the resulting reaction mixture (may be a reaction solution)
Implementation Method 3
recrystallizing a crystal of a tetrahydrofuran solvate of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea or a salt thereof using an alkyl alcohol and one solvent selected from the group consisting of dimethylsulfoxide, dimethylformamide (N,N′-dimethylformamide, in the present specification, to also be referred to as DMF) and dimethylacetamide (N,N′=dimethylacetamide, in the present specification, to also be referred to as DMAc)
Data Source
AI summary
The present invention provides a production method of a thienopyrimidine derivative or a salt thereof which has a gonadotropin releasing hormone (GnRH) antagonistic action with high quality in high yield. The present invention provides a method of producing a thienopyrimidine derivative, which comprises reacting 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl) thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione or salt thereof, 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof, and the like.