\\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Title-R1d.png Petr Beňovský SYNTHETIC ROUTE DESIGN AND SELECTION \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GENERAL ISSUES •Academia vs. Industry (even more coordinated approach involving large numbers of chemists and supporting personnel towards a common goal); •Moreover, “in the meantime“, under high time pressure and stress, process people need to continually improve their expertise and capability for the effective design of new synthetic routes; •Plan ® Do ® Audit cycle ® ® ® Select •Understand sources, available time, limitations, priorities, risks, quality, quantity, budget, … • \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E C T Butters, M. et al Chem. Rev. 106, 3002 (2006) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E C T Butters, M. et al Chem. Rev. 106, 3002 (2006) Criteria Subcriteria Potential Issues SAFETY Process, health Thermal risk, carcinogens, sensitisers ENVIRONMENTAL Waste, environmental hazard Inceneration of solvents, aquatic toxins, ozone depleting chemicals LEGAL Intellectual property Indication, compound protection, process ECONOMICS Cost of goods, production cost, concentration Length of the synthesis, cost of operations CONTROL Control of quality parameters, P-CH parameters Meeting specifications, GMP requirements THROUGHPUT Time scale of manufacture Continuity of steps, operations, transfer, availability of chemicals \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S A F E T Y E L E C T \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E N V I R O N M E N T A L L E C T Very difficult to develop totally sustainable process with a low (or none) environmental impact Always depends on the production volume and particular hazard \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E G A L E C T In civilized countries the development and commercialisation of API must be performed without breaking laws or infringing valid intellectual property; Legal issues can arise any time and patent litigations are pretty common; •Regulated or banned substances •Using unacceptable quantities •Transportation of hazardous materials •Materials with third-party restrictions •Patent infrigement \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E G A L E C T •Compound protection • •Procedural protection • •Utilization protection • Novelty (in comparison with the state of art) Inventive step Industrial use \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E G A L E C T Patent application •national •regional •worldwide Patent does not automatically give you a right to use – you still have to make sure that it is NOT infringing the other party intellectual property \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E G A L E C T ADR \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E G A L E C T \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E C O N O M I C S C T The key factors determining the economic viability: •Cost of goods (CoG) •Price of the product •Marketing costs •Product and/or technology licensing •Investment CoG – the total cost involved in manufacture of a drug product (API manufacturing, formulation, packaging) expressed as a percentage of the selling price of the drug \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E C O N T R O L T Compliance with valid guidelines of authorities for particular region (FDA, EMEA, ASEAN, ICH) Specification that defines the acceptable quality – a must for the registration process; Impurities – known, unknown Mutagenic impurities – ICH M7 guideline Solvates, stability (DVS, TGA) Stability tests, enforced degradation studies Polymorphism, Heavy metals DoE, QbD, PAT \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E C T H R O U G H P U T The amount of material that can be manufactured in unit time; Usually identified in the late stage of development for already established procedure; \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA S E L E C T H R O U G H P U T •Chemical yield often can be improved through a deeper undestanding of kinetics and mechanism; •Reducing the number or the length of the most time consuming operations will improve throughput – telescoping; •Poor solubility could be a problem; • • •Protecting – deprotecting sequences; • \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA - THROUGHPUT \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SELECT CRITERIA - THROUGHPUT \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png DEVELOPMENT PHASES \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CLINICAL PHASES Phase 1 – safety screening (20-80 healthy volunteers) – safe dosing is determined and possible side effects identified; Phase 2 – testing protocol is formulated (100-300 patients) – efficacy determination and further details about safety ; Phase 3 – Final testing (1000-3000 patients) – desired effect confirmed, monitoring of side effects, comparison with known similar drugs; after successful completion of this phase a drug is usually approved and registered. Phase 4 – Following studies after approval – gathering further pieces of information about risks, advantages and optimal dosing \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM Bristol-Myers Squibb Highly selective thromboxane A2 receptor antagonist (antithrombotic and anti-ischemic properties) Mueller, R.H. Process Chemistry in the Pharmaceutical Industry, p.37, Marcel Dekker Inc. 1999, ISBN 0-8247-1981-6 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM Potential new drug candidates: \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM Large supply of the product made in Kilo Lab, but at the same time first candidate SQ-28668 failed in the clinical studies; Next drug candidate was chosen (SQ-30741) – but exhibited extensive first-pass metabolism in clinic and further work was halted; 17 kg of the product still remained unutilized; Finally, BMS-180291 selected as promising drug candidate (the product proved very useful for the start in Kilo Lab campaign). \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM SUMMARY (so far): 23 steps, synthesis is convergent but the longest linear sequence consists of 16 steps; Overall yield < 3% 10 steps involve oxidation stage adjustment Resolution process BMS-18029 seemed to be promising drug candidate in preliminary tests „Quick-fixes“ in original route to get more material (20 kg by a combination of Kilo Lab and Pilot Plant efforts); In the meantime Process Research activities started to identify a better route \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM Model alternative Diels-Alder approach: Would require synthetic approach to starting propargylic derivative \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM Stereoselective approaches (to avoid resolution): \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM More efficient than the original synthetic pathway; Safety concerns; The yield in the Grignard to lactone conversion was lower than practical \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM With S-valinol or S-phenylglycinol auxiliaries 65% yield; 72% ee; Relatively inexpensive chiral auxiliary S-methylbenzylamine provided selectivity 94 : 6 (>99 : 1 after crystallization) in 89% yield. Serine derived chiral auxiliaries gave lower yields and stereoselectivity. \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM Improved efficiency: \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM Still improving efficiency: \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png A PRACTICAL SYNTHESIS OF IFETROBAN SODIUM SUMMARY: 12 convergent steps; 3 oxidation-reduction reactions left from 10; 83 researchers. Overall yield 28%;