ROUTE SELECTION|PHARMA PROCESS CHEMISTRY

1. 1
ROUTE SELECTION
MPC-2041 PHARMACEUTICAL PROCESS CHEMISTRY
UNIT PROCESSES-II
REACTION PROGRESS KINETIC ANALYSIS
BY
PROTTAY DUTTA

2. Learning objectives
❑ Be aware of practical techniques used within route selection.
❑ Be able to balance a range of criteria to make a decision on which is the
'best' route.
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3. Contents
❑ Introduction.
❑ Learning Objectives.
❑ Type Of Route Selection.
❑ Characteristics.
❑ Recap Of The Select Criteria.
❑ Application Of API Synthesis.
❑ Route Selection- Key Strategies.
❑ Software Tool For Route Selection.
❑ Reference.
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4. Introduction
❑ Route selection is the foundation of developing new products and
processes.
❑ Selecting the optimal route to make your molecules can have a major
impact on both the environmental impact of your route as well as the
cost of goods.
❑ 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.
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5. Type of route selection
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.
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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. Optimal routes
❑ Optimal route are developed to manufacture inexpensive bulk drug
substance or final product over the lifetime of a patent or longer.
❑ Laboratory processes are developed and examined on scale, and they
evolve into optimal routes that are cost-effective, rugged, and forgiving.
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8. Characteristics of optimal route-
❑ Technical Feasibility -Confidence in a large-scale route is usually earned
after studies in a pilot plant setting.
❑ Availability of suitable equipment- Often routes are chosen in order to
use existing large-scale equipment because of the great costs of buying
and installing new equipment (and plants).
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9. Continue
❑ Long term availability of inexpensive reagents and starting materials- To
avoid having to depend on one supplier, companies are wise to identify
several sources of key reagents.
Starting materials, and intermediates, Cost, quality, and reliable delivery
are critical parameters.
❑ Convergent Synthesis- When a synthetic route incorporates convergent
sub routes, the total amount of intermediates required for the
preparation of a product can decrease dramatically .
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10. Continue
❑Using telescopic work ups- Isolating intermediates has many potential
disadvantages.
▪Isolation is usually costly and invariably leads to some loss of valuable
material.
▪On a manufacturing scale, isolating intermediates and API requires about
50% of personnel time and about 75% of equipment financial outlay .
❑Minimizing Impact from Protecting Groups- Product cost rise due to the
cost of reagents and to the additional steps resulting from applying and
removing protecting groups.
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11. Continue
❑Minimized Number of Steps- To decrease the number of operations, an
obvious remedy is to redefine the route by using different starting
materials that require fewer steps to produce the product.
❑Avoiding Adjusting Oxidation States- Adjusting oxidation levels causes
unnecessary expenses of time and money if instead intermediates at the
suitable oxidation level can be used in the synthetic sequence.
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12. Continue
❑Enantiospecific and Stereo-specific reaction - Resolution of enantiomeric
materials returns at best only 50% of the mass input, and the remaining
material must be converted to product or sent for disposal.
❑Incorporating Unexpected Processing -The cost-efficient process will
take advantage of unusual occurrences encountered during research and
development .
▪A slow reaction at a sterically congested site may eliminate the need for a
protecting group.
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13. Continue
❑Incorporating rearrangements- Rearrangements can also be used to
incorporate key elements of stereochemistry and regiochemistry from
simpler molecules.
❑Focusing on a common penultimate or key intermediate - Considerable
process research and development may occur on several different routes
over time. Usually these routes converge at the penultimate intermediate
or key late intermediates.
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14. Continue
⮚Facile Rework for Final Product and Intermediates- The expected quality
of final product and intermediates is not always achieved. Cost-effective
routes include rework procedures to upgrade batches.
Patent Protection for Manufacturing Route- Patents allow the assigned
company to reap the benefits of selling their researched product without
competition for a finite period; the period varies according to the country
of origin.
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15. Recap of the SELECT Criteria
❑S – Safety – removal/minimization of reactive hazards and toxicity and
hazardous reagents/solvents.
❑E – Environmental – removal/minimization of reagents/solvents harmful
to the environment; volume and nature of waste.
❑L – Legal – no infringement of existing intellectual property.
❑E – Economics – minimize cost of goods/meeting cost of goods target.
❑C – Control – meeting quality specifications; process must be under
control, validated, consistent impurity profile.
❑T – Throughput – availability of raw materials; manufacturing time;
maximized space time yield.
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17. Application of API synthesis.
❑There is almost always more than one route and each group will have
given starting materials and intermediates
❑But also a choice of reagents, reaction types and solvents to construct
the products.
❑Sometimes route selection can be relatively simple, as we can see from
this molecule here, the choice is fairly straightforward.
❑Essentially four building blocks, all of these building blocks are
commercially available at scale and the key task is really order of
connection and it's a convergent, not linear, process.
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18. A synthetic pathway to a desired
molecule product.
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19. ❑We can see the essentially four building blocks being highlighted here.
Key task is order of connection-convergent not linear.
Reaction 1, reaction 2, reaction 3.
But sometimes route selection can be much more challenging.
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20. Continue
❑If we look at this molecule, Ticagrelor, it's altogether more thought
provoking.
❑It has a number of challenging synthons: highly functionalized Cyclo-
pentane ring a novel heterocyclic core and an Amino cyclopropyl benzene
fragment.
❑It also has the complexity of six chiral centers that have to be controlled
and at the start of the project, none of these main synthons were
commercially available.
❑So a much more challenging structure.
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21. Continue
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22. Selecting the optimum route for a
given API is often an iterative task.
❑There may be several, or many, paper routes and these need to be
evaluated on paper the short ones tested in the lab.
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23. The environmental impact of a
process.
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24. The route of foundation
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25. Processing cost.
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26. Revenue stream of an API product.
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27. Driving performance through route
selection.
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28. Route selection- key strategies.
❑Use catalytic reaction metal, chemo / bio-catalysis.
❑Identify risk and remove/minimize use of hazardous materials.
❑Avoid isolation and drying.
❑Process intensification.
❑Consider recycle and reuse.
❑Effective abatement and waste treatment measures.
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29. Software tool for route selection
❑Route selection is at the foundation of designing a route that meets-
▪ Operational.
▪ Environmental.
▪ Legal and economic factors.
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30. Some of the tools that are available to
provide information and assistance with
route selection.
❑ SciFinder.
❑ Reaxys.
❑Science of Synthesis -Information arranged according to structure .
❑Prous Science Integrity- Compounds which have entered clinical trials.
❑Smartch- Database of bulk chemicals .
❑Spresi .
❑Wiley Chem Planner.
❑Google Scholar .
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31. Questions and answer.
❑What is the route selection? Describe the type and characteristics of route
selection .(Ans- 4-15)
❑Describe the criteria of route selection . (Ans- 15,16)
❑Describe the application and synthetic pathway of molecule. (Ans-17-21)
❑What is the environmental impact of process chemistry?(Ans- 23)
❑Explain, what is strategy of root selection?(Ans- 28)
❑Distributed some knowledge on the software used in chemistry.(Ans- 30)
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32. THANK YOU
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Reference-
▪http://learning.chem21.eu/media/pdf/route-selection-a4.pdf
▪https://sci-hub.tw/10.1016/B978-012059475-7/50005-3