Budesonide 21-Phosphate Synthesis via Room-Temperature Phosphorylation
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Solution Overview
Problem
Budesonide, a crucial glucocorticoid steroid for asthma and COPD treatment, is practically insoluble in water, leading to stability issues and unsuitability for delivery via electric nebulizers due to its low water solubility and rapid decomposition in hydroalcoholic solutions.
Innovation Solution
A novel one-pot process using tetrabutylammonium dihydrogen phosphate and trichloroacetonitrile at room temperature to synthesize budesonide 21-phosphate and its disodium salt, which is more stable and water-soluble, eliminating the need for harsh conditions and expensive procedures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If budesonide is dissolved in hydroalcoholic solutions to improve water solubility, then solubility is improved, but stability deteriorates because large amounts of budesonide are decomposed within a short time
Solution Approach 1:
The invention changes the chemical structure parameter of budesonide by introducing a phosphate group at the 21-position, transforming it from budesonide to budesonide 21-phosphate. This structural modification fundamentally alters the solubility and stability parameters, enabling the compound to be water-soluble and stable simultaneously, thus resolving the contradiction between solubility improvement and stability maintenance
Solution Approach 2:
The invention creates a composite molecular structure by combining the budesonide core with a phosphate group, forming budesonide 21-phosphate. This composite structure integrates the therapeutic properties of budesonide with the water solubility and stability characteristics of phosphate esters, simultaneously achieving both solubility and stability requirements
2Quantity of substance
If aqueous suspensions are prepared to deliver budesonide, then water solubility is improved, but device complexity increases due to sedimentation requiring chemical additives or vigorous stirring
Solution Approach 1:
By modifying the chemical structure of budesonide to budesonide 21-phosphate, the invention changes the solubility parameter from insoluble to water-soluble. This allows the formulation to be a clear aqueous solution rather than a suspension, eliminating sedimentation issues and the need for stirring mechanisms or complex additive systems
3Manufacturing precision
If diphosphoryl chloride is used for phosphorylation at -40°C to synthesize budesonide 21-phosphate, then product purity is improved, but energy consumption increases due to harsh conditions and expensive procedures
Solution Approach 1:
The invention changes the reaction temperature parameter from -40°C to room temperature, and replaces diphosphoryl chloride with trimethylsilyl dihydrogen phosphate as the phosphorylating agent. These parameter changes maintain product purity while dramatically reducing energy consumption and eliminating the need for expensive specialized procedures
Solution Approach 2:
The invention replaces the expensive and hazardous diphosphoryl chloride reagent with the cheaper and safer trimethylsilyl dihydrogen phosphate. This substitution reduces both material cost and energy requirements for maintaining harsh reaction conditions, making the process more economically viable
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 process provides budesonide 21-phosphate disodium salt with improved yield, stability, and solubility, ensuring long-term stability and suitability for aqueous solutions without the production of strong acids, making it manageable and cost-effective.
Implementation Method 1
reacting budesonide with tetrabutylammonium dihydrogen phosphate and trichloroacetonitrile to obtain the compound of formula (II)
Data Source
AI summary
The present invention relates to a new process for the preparation of budesonide 21-phosphate and its disodium salt.