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Custom Synthesis Case Studies

A Medicinal Chemistry Challenge

A client needed to synthesize a pro-drug based on a well known over-the-counter analgesic. The properties sought by the client was an increase in the water solubility of the drug which would increase its bioavailability and decrease the require dosage. The key feature in the pro-drug which would offer these properties was a readily hydrolyzed phosphate ester attached by a carbonyl group. The client outsourced this to a custom synthesis firm who made several unsuccessful attempts at preparing the targeted molecule. When Cyanta was awarded this project, our chemists redesigned the synthetic route, applied rigorous anhydrous techniques and prepared a preliminary batch in about one month's time. The nature of the pro-drug made it both water soluble and readily hydrolysable, this rendered traditional analytical methods useless for assaying the potency and purity of the pro-drug. A quantitative 31P NMR method was developed by Cyanta as part of the release analysis. Several additional batches were prepared and a stability study was put in place.

Process Development Leads to Patent

A client required process development of a drug candidate, their medicinal chemistry group had a lead compound prepared from a 5 step route using commercially available starting materials. The second step was difficult to control. It had an exothermic tendency after a variable induction period. The third step and the final step required chromatographic purification. The chemists at Cyanta improved the synthesis route by finding an alternative to the exothermic step, selected different reagents for the third step which allowed for purification by recrystallization (and eliminating the chromatography) and modified reaction conditions for the final step which also allowed for purification by recrystallization. We produced several kilograms using these improvements. A US patent was awarded for this work and the our chemists were listed as co-inventors.

Successful Synthesis of Five Impurities

A client was in the late stages of a NDA filing and their API producer had 5 process related impurities, which exceeded permissible amounts, in their production batches. These impurities were known compounds, however, reliable procedures for their synthesis did not appear in the literature. Each of the impurities had from 5 to 7 functional groups present which made each target a synthetic challenge by itself. The team at Cyanta developed synthetic procedures for all 5 impurities and prepared sufficient quantities for the client to perform toxicology studies and accomplished the synthesis against an aggressive timeline.

A Successful Scale Up of a 7 Step Synthesis

A client was developing a lead compound based on a 7 step synthetic route with 5% overall yield. The process was demonstrated on a 100 g scale, initial testing showed promise and the next phase of development required 3 kg of material. Some of the challenges in the 100 g route, aside from the low overall yield, were purifications of intermediates using chromatography and mixed solvent recrystallizations. The mixed solvent recrystallizations were quite vexing since they were not always reproducible. The chemists at Cyanta improved the process by: purifying one of the intermediates as a salt; controlling a halogenation step with careful in-process monitoring; and increasing the yield of the penultimate product by altering the stoichiometry and the isolation method. Ultimately, the improvements in the process increased the overall yield from 5% to 18%. The client received the 3 kg batch they required and a process that is commercially viable.