Route selection

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. 2

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. 3

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. 4

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. 5

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. 6

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. 7

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). 8

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 . 9

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. 10

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. 11

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. 12

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. 13

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. 14

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. 15

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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. 17

18. A synthetic pathway to a desired molecule product. 18

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. 19

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. 20

21. Continue 21

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. 22

23. The environmental impact of a process . 23

24. The route of foundation 24

25. Processing cost . 25

26. Revenue stream of an API product. 26

27. Driving performance through route selection . 27

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. 28

29. Software tool for route selection Route selection is at the foundation of designing a route that meets- Operational. Environmental. Legal and economic factors. 29

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 . 30

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) 31

32. THANK YOU 32 Reference- http://learning.chem21.eu/media/pdf/route-selection-a4.pdf https://sci-hub.tw/10.1016/B978-012059475-7/50005-3