Crystalline Doripenem Intermediate for Purification Yield
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Solution Overview
Problem
Existing methods for preparing doripenem face challenges with the purification and storage of intermediate compounds, which are often amorphous foamy solids, leading to low yields and increased production costs due to complex de-protection steps and multiple protecting groups.
Innovation Solution
A doripenem intermediate compound with a single protecting group, represented by formula (XIV), is developed, which is crystalline and easier to purify, using specific acid-alkali proton conditions and X-ray diffraction patterns to ensure high purity and yield, and a process involving condensation reactions and catalytic hydrogenation for efficient production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If doubly-protected doripenem intermediate compound (VII) is prepared through condensation reaction, then the intermediate can be obtained with 88% yield, but the intermediate becomes an amorphous foamy solid that is difficult to purify and store, reducing subsequent de-protection yield to 73%
Solution Approach 1:
The patent changes the physical state parameter of the intermediate compound from amorphous to crystalline by modifying the protection strategy. The crystalline form enables easy filtration and purification, directly resolving the contradiction between obtaining high yield and maintaining ease of manufacture.
Solution Approach 2:
The patent segments the protection strategy into two stages: first using a protection group that forms crystalline intermediates for easy purification, then removing that protection before the final de-protection step. This segmentation allows each stage to be optimized independently.
2Manufacturing precision
If column chromatography is used to purify intermediate compound (VII), then the yield of de-protection step improves to 84.8%, but production costs increase and production efficiency decreases
Solution Approach 1:
The patent changes the physical form parameter from amorphous to crystalline, which fundamentally alters the purification method from complex column chromatography to simple filtration. This parameter change simultaneously achieves high purity and maintains high production efficiency.
Solution Approach 2:
The patent employs a disposable protection group strategy where the first protection group is intentionally designed to be easily removable and form crystalline structures, serving as a temporary purification aid that is discarded in the process.
3Manufacturing precision
If methanol solvate crystal (VIII) is obtained by adding methanol to intermediate solution, then purity above 98% is achieved, but operation time extends to 8 hours, reducing production efficiency
Solution Approach 1:
The patent changes the solubility parameter by selecting a specific solvent system where the intermediate has low solubility, enabling rapid crystallization. This parameter optimization reduces crystallization time from 8 hours to a much shorter duration while maintaining high purity.
Solution Approach 2:
The patent creates a composite crystalline structure through co-crystallization with a specific solvent molecule, forming a stable crystal lattice that precipitates rapidly and filters easily, simultaneously achieving high purity and short processing time.
4Stability of the object's composition
If tri-protected doripenem intermediate compound (X) is prepared, then de-protection complexity increases with three protecting groups, but amorphous foamy solid formation is avoided
Solution Approach 1:
The patent segments the protection groups into two functional categories: a first protection group that ensures crystalline formation and stability, and a second protection group that is removed in a separate step. This segmentation reduces de-protection complexity while maintaining stability.
Solution Approach 2:
The patent performs preliminary removal of the first protection group before the final de-protection step, preparing the intermediate in a specific form that is easier to handle and process, thereby simplifying the overall de-protection process.
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 novel doripenem intermediate compound simplifies the de-protection step, improves yield, reduces production costs, and facilitates industrial-scale production by being easily purified and stored, ensuring high-quality doripenem production.
Implementation Method 1
subjecting a parent nucleus compound (II) of carbapenem antibiotic compounds and a side-chain compound (XV) of doripenem to a condensation reaction in an organic solvent under the action of a base
Implementation Method 2
reacting the reaction mixture or product obtained in the step (1-1) with the water solution containing HX to obtain the doripenem intermediate compound
Implementation Method 3
preparing doripenem represented by formula (I) in a solvent under the action of a catalyst by using the doripenem intermediate compound according to any one of claims 1-4 through de-protection reaction where the catalytic hydrogenation is performed
Implementation Method 4
X-ray diffraction pattern of the crystal comprises the diffraction peaks at the following angles of 2θ
Data Source
AI summary
The present invention provides a doripenem intermediate compound shown by formula (XIV), wherein PNB is p-nitrobenzyl, and HX is an acid; and when HX is a monobasic acid, n=1; and when HX is a polybasic acid, n=2. The present invention also provides a process for preparing the doripenem intermediate compound (XIV). In addition, the present invention provides a process for preparing doripenem (I) from the doripenem intermediate compound (XIV) in a simple manner, with a high yield and low production costs. The new mono-protected doripenem intermediate compound provided in the present invention contains only one protecting group, reducing the difficulty and complexity in the subsequent de-protection step by catalytic hydrogenation, increasing the yield of the catalytic hydrogenation reaction, and thus reducing the production cost of the final product. The process is easy to operate and suitable for industrialized production.