This document discusses reaction progress kinetic analysis and strategies for selecting optimal and cost-effective routes for scale-up synthesis. It notes that route selection considers environmental impact, legal intellectual property, economics, control over product quality specifications, and throughput. Expedient routes are employed early in drug development to expedite material for testing and consider familiarity, technical feasibility, and equipment availability. Characteristics of cost-effective routes include technical feasibility, suitable equipment, and availability of inexpensive reagents and starting materials. The document provides examples of reagent and solvent selection strategies and families of reagents useful for scale-up, such as bases, oxidations, and catalytic reagents.

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Reaction Progress Kinetic Analysis
Presenting by:
Mr. Purushotham K N
Asst. Professor
Dept. of Pharm. Chemistry
SACCP, B.G Nagar
2022-2023

2. Contents:
• Reaction progress
• Expedient route
• Characteristics of expedient routes
• Characteristics of Cost-effective Routes
• Solvents selection
• Families of Reagents Useful For Scale-up
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3. Reaction progress
• Route selection is at the foundation of developing new products and processes. Selecting the
optimal route to make molecules can have a major impact on environment and cost of
product. Inventing, developing, and commercializing new chemistry and products rapidly is a
key for sustained profitability in the agrochemical, fine and specialty chemical, and
pharmaceutical markets. Usually there are many synthetic pathways, or routes, to synthesize a
given structure. For each given route there is choice of starting materials, intermediates
reagents and solvents to synthesize the products.
• Route selection is a complex process, and synthetic routes can change during the
development pipeline of an API, and post launch as part of life cycle management activity.
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4. • For route selection following factors should be considered:
1. Environmental impact: the volume and nature of waste.
2. Legal: ensuring intellectual property rights (breach anyone's patents).
3. Economics: lower cost of target molecule.
4. Control: Meet the quality specifications.
5. Throughput: The availability of raw materials, manufacturing time, make enough
material to satisfy commercial demand.
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5. • Expedient route
• Expedient route are employed early in the development of a drug candidate to expedite
the preparation of material that is required for initial testing. Making this material in a
timely fashion is necessary to promptly assess the feasibility of developing the
compound.
1.Familiarity: time and availability of reagent
2.Technical feasibility- Technology known
3.Availability of equipment
4.By this route target molecule can be produced on large scale
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6. Characteristics of expedient routes
Familiarity:- Routes and reagents may be selected on the basis of an established
route, the chemist's familiarity in working with particular reagents.
Technical Feasibility:- Confidence is needed in order to justify risking precious
starting materials, reagents, and research time.
Availability of Suitable Equipment:-The availability of equipment will influence
route selection.
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7. Characteristics of Cost-effective Routes
1.Technical Feasibility : robust method is produce and control parameter like PH ,
raw material , equipment, temperature , reaction time .
2.Availability of Suitable Equipment : specilised equipment or produce from vendor.
3.Long-Term Availability of inexpensive Reagents and Starting Materials : select
supplier providing good quality reagent. Cost, quality, and reliable delivery are
critical parameters.
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8. • Strategies for Selection of Optimal Routes/Cost effective Routes
1.Use less intermediate and less steps in synthesis .
2.Using Telescopic Work-up - It is called one step synthesis in this intermediate are isolated and purified
to increase product quality and time for synthesis .
3.Minimizing Impact from Protecting Groups - Protective group temporary block active sites of
compound and avoid unwanted reactions .
4.Use of Enzymatic transformations- it removes protecting groups Minimized Number of Steps: reduce
step to decrease time, cost.
5. Double reaction, Tandem Reaction, Multiple reaction Avoiding Adjusting Oxidation States: Use
intermediates at the suitable oxidation level.
6.Minimized Environmental Impact - waste generated, incorporate Green Chemistry Enantiospecific
and Stereospecific Reactions: Chemo selective, Regioselective , Enantioselective, Diastereoselective. 8

9. • Selection of raw material
A)Reagent selection - After route is selected then important step is to select the correct reagent for selected
route. Reagent selection can have a critical effect upon reaction scale-up safety, especially if things go wrong.
The ideal reagent should produce: The desired product in high yield in the expected time frame
 Minimal effort needed for work-up and isolation of the product.
 Decreased Cost and easy availability, case of handling and waste disposal considerations
Impurity profiles vary from lot to lot and from manufacturer to manufacturer. Perform front-runs first to
verify results before proceeding.
If using large equivalent excesses of a reagent, try running a more concentrated reaction with less
equivalents.
Use reagents that allow for better stoichiometric control and safer chemical handling and storage.
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10. Examples:
o Use NH4Cl and base rather than NH3 dissolved in Dioxane.
o Use NH4NO3 and H2SO4 rather than HNO3 and H2SO4
o Use dimethylamine hydrochloride and base rather than dimethylamine
dissolved in water, THF, or methanol.
o Use TMS diazomethane or generate diazomethane in diethyl ether rather than
distilling diazomethane.
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11. Avoid sensitive intermediates. Carefully determine how you will drive a reaction to completion.
Use reactions that will allow you to easily add more reagents (to drive reactions forward) rather
than having to create more of an intermediate.
If possible, use reagents that can make workups and purifications cleaner and easier. This can
lead to cleaner reactions, less intensive purifications, lower flammable solvent usage, lower fire
hazard, and less expenditure of time. Ultimately, efficiency and safety are increased.
• Examples:
o For Mitsunobu or Wittig reactions, use trimethyl phosphine (Me3P) (1M solution) rather than
triphenyl phosphine (Ph3P); Me3P=O is water-soluble and can be washed away; Ph3P=O is
sometimes difficult to remove during purification.
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12. o Use N,N-Dimethylethylenediamine to scavenge excess acid chlorides, acrylates, mixed
anhydrides. Then wash away with a simple acid
• wash during workup.
N,N-Dimethylethylenediamine
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13. • Solvents selection
• Be aware of the flammability of solvents around the equipment you choose, and take
the appropriate precautions.
 If possible, choose solvents that will boil before the product decomposes. This helps
to prevent the formation of tar, impurities, and other side products.
 Be aware of the dangers (explosions) from concentrating peroxide-forming solvents.
When working with >1000 ml of peroxide-forming solvent, check peroxide levels
• when the volume of solvent has been reduced to 10-20% of the original volume.
 Use freshly distilled or purchased solvents, especially if anhydrous conditions are
needed.
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14.  Avoid highly volatile solvents with low boiling points and peroxide-forming issues. Use of
these solvents poses fire and explosion hazards, especially during operations involving
transfers, heating, and concentrating. Highly volatile solvents are also prone to concentration
changes (e.g., running the reaction vessel dry).
o Avoid THF(tetrahydrofuran) and use 2-MeTHF (less peroxide issues, slightly higher b.p.,
and more environmentally friendly);
o Avoid diethyl ether (Et2O) and use methyl tert-butyl ether (t-BuOMe) (less volatile, higher
b.p., less peroxide issues);
o Avoid hexanes and use heptanes (higher b.p., less toxic, less volatile)
o Avoid dichloromethane CH2Cl2 & trichloromethane CHCl3 and use 1,2-dichloroethane
(higher b.p., ALL halogenated solvents have toxicity issues).
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15.  When performing air-sensitive reactions (e.g., Suzuki, Buchwald) sparge the solvents
(run a steady stream of bubbling inert gas through the solvent via a 12-18” needle
while in the reaction vessel). This is safer and works better than degassing with
vacuum (freeze-pump-thaw method). Sparge solvent mixture for 30 minutes with
• stirring before adding sensitive reagents, then sparge for another 5-10 minutes after
addition but before heating.
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16. • Families of Reagents Useful For Scale-up
1. Reagents for Deprotonation - n-Butyl lithium, NaH are most commonly used for
deprotonation of weakly acidic molecules
2. Alkoxide Bases – potassium tertiary buroxide is often used as a moderately strong base
3. Amine Bases – Triethylamine, tributylamine (Bu3N) commonly used to scavenge acids
generated during reactions.
4. Oxidations – most troublesome reactions to scale up due to toxicity and hazardous
chromium trioxide CrO3, Pt/O2, H2O2.
5. Reductants – Pt/H2, sodium borohydride (NaBH4)
6. Catalytic reagents - Sharply decrease costs of both reagents and waste disposal and can
increase productivity. – catalytic hydrogenation is used for scale up in industries. Rh-
TPPTS (3,3′,3″-Phosphane triyltris(benzenesulfonic acid) trisodium salt).
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17. 7. Polymeric reagents – ion exchange resins- convenient filtration
removes the polymers and facilitates work-up.
8. Biocatalysts as Preparative Reagents- often used to prepare molecules
with two or more chiral centre.
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18. THANK YOU
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