化学药实用工艺研究Practical-Process-Research-and-Development—冯鑫2017.8.21

1 Route Slection
A Health, SAFETY, and Environmental assessment is a critical criterion in our process development.... It’s got to be dealt with, and it’s not taken lightly. If problems are insurmountable, or If there is danger to the environment, a synthesis will be replaced.”
Safe: posed no chemical reaction hazard
Liability increases with scale
No shipping restrictions
CH3Li in Et2O
No purchasing restrictions
Time is required to obtain licenses, the chemical could be used to make illegal drugs
Example
Dissolve substrate in DMF, DMSO, or acetone Change Boc for benzyl High-throughput
Cost estimates
• Cost = raw material + manufacturing + waste disposal
Example
Example:
Guidelines for developing biocatalytic processs
Quickest to effect源自文库1 2 3
Change
Screen medium Modify starting material Screen biocatalysts
1-5: Catalysis
With catalytic reactions involving expensive catalysts cost-efficient route will recycle the catalysts.
1-6: Direct Isolations
Direct isolation minimize consumption of RM, energy, time and labor. And it is very convenient both for plant and Kilo-lab.
1-1: Analyzing Waste Streams (First Principle)
• It is far better to prevent waste, not just reducing waste.
• Routes with fewer steps require smaller quantities of starting materials, solvents, and reagents, and require less labor.
1-4: Reduce use of Protecting groups
The route with the fewest steps may be the greenest and cheapest and the fewest opportunities for errors.-----difficult!!!!!
• Previously fermentations were considered for complex molecules such as antibiotics.
• Biocatalysts have been developed for synthetic purposes and it was usually associated with enzymes: transaminases
Non-toxic
PPE is time-consuming, cumbersome, inconvenient
If highly toxic, non-volatile
Filtration/ crystallization/recrystallization/slurry is the favorite.
Example
Biotransformations
• Biotransformations provide exciting opportunities for changing synthetic routes.
2 Reagent Selection
Some ideal characteristics of reagents
characteristic
Comments or examples
Specific for the desired synthetic transformation
Isolation is easier from high-yielding reaction
Practical Process Research and Development
冯鑫 Xin Feng 2017/8/21
Content：
• 1：Route Selection • 2: Reagent Selection • 3: Solvent Selection • 4: Running Reaction • 5: Optimizing the reaction by minimizing impurities • 6: Tools for Purifying the product
1-2: Atom Economy
Atom economy is not the primary consideration for manufacturing in the pharmaceutical industry
1-3: Less Hazardous Chemical syntheses