Incontro per l orientamento alla tesi sperimentale

Transcription

1 Corso di Laurea Magistrale in Chimica e Tecnologia del armaco Corso di Laurea Magistrale in armacia Incontro per l orientamento alla tesi sperimentale Prof.ssa Daniela Lanari 22 ovembre 2017, Aula A via del Liceo Dipartimento di Science armaceutiche

2 Chimica rganica Corso di LM in armacia Co-docenza con il Prof. Massimo Curini Teaching Contact info Daniela Lanari Via del Liceo,1 Tel: mail: Materials for Renewable Energy Sources Corso di LM in Scienze Chimiche Curriculum di Chimica rganica ed Environmental and Sustainable Chemistry Teaching Daniela Lanari, PhD ptimization of organic processes to minimize waste production 1. Heterogenous catalysis 2. Alternative reaction medium Research High yields (chemical) Benign reaction conditions (environmental)

3 EPA Green Chemistry Challenge: 2017 Greener Synthetic Pathways Award Merck & Co., Inc. Letermovir: A Case Study in State-of-the-Art Approaches to Sustainable Commercial Manufacturing Processes in the Pharmaceutical Industry The chemical process based on a late-stage chiralresolution to obtain the desired steroisomer. Room for improvement low overall yield of 10% the use of nine different solvents high palladium loading in a C-H activated Heck reaction little opportunity to recycle solvents or reagents. Antiviral drug candidate for the treatment of CMV infections, currently in phase III clinical trials. Improvements of the new process: Six novel asymmetric reactions to introduce the stereogenic center (minimal use of protecting groups, preventing waste on the molecular level) Substitution of non-sustainable and costly transition metal catalysts (e.g. Pd, Ru, Rh) as well as expensive chiral ligands with a new stable and fully recoverable organocatalyst Improvements of the new synthetic procedure increases the overall yield by more than 60% reduces raw material costs by 93% reduces water usage by 90%.

4 UR APPRACH T GREE CHEMISTRY Set -up organic processes to minimize waste production Heterogeneous Catalyst Easy toseparate Recoverable Re-usable Supported Catalyst PS Commercially available Taylored-made Amb- PS Journal of Catalysis, 2014, 309, PS-DABC 2 Adv. Synth. Catal. 2012, 354,

5 UR APPRACH T GREE CHEMISTRY Target: realize more efficient processes that may not be performed in classic organic media γ-valerolactone (GVL) b.p= C; ε= 36.5 Polar aprotic solvent Validalternative to toxicdm or DMP Safer non conventional reaction media 1-Ethyl-3-methyl imidazolium chloride 1.Biomassderived 2. Ionic Liquids 3. Solvent-free conditions Thermal stability on flammability Low vapour pressure Interesting solvent properties Use in extracting distillation( with Prof.Marcotullio) Exploit new reaction pathways Closer interaction between reactants

6 GVL as medium for Pd-catalyzed couplings Heck Reaction Ar-I + Pd/C 1 mol% TEA (1 eq) GVL 1 M Ar Very low Pd content Medium T ( C) Time (h) Pd content (ppm) GVL GVL min 6.3 GVL min 3.9 MP min 835 MP min 279 DM min 50 Green Chem. 2015, 17,

7 1.0 PS-DABC 2 for Aza-Michael Reactions 1 mmol 96 mg + 20% PSDABC 2 32 mg H 2, 0.5 ml TMS mmol 172 mg PS 18 h, 30 C 3 PS-DABC mmol 132 mg yield: 95% AcEt 1.0 ml 900 mg E-factor = 7.8 Total Waste (g)/ Product (g). (96 mg mg mg 132 mg)/ 132 mg = 7.8 A reduction of 63-90% compared to literature procedures Up to 5 cycles without loss in efficiency Vaccaro etal.j. rg. Chem.2006, 71, 9536:E-factor21.5(on 1 mmolscale) Miller etal. rg. Lett. 1999, 1, 1107: E-factor>100(on 1 mmolscale) Adv. Synth. Catal. 2012, 354, highlighted in SYACTS 2012, 689

8 ew PS-TBD catalysts for the synthesis of Warfarin and its analogues Warfarine: mostusedanticoagulantworldwidesold asracemate(coumadine TM ) R=H Warfarin R=4-2 s Acenocoumarol(Sintrom ) R= 4-Cl R= 4-Me Three newpolystyrene-bound1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) havebeen synthesized(ps-tbd) Superioractivitycomparedtocommerciallyavailablec-PS-TBD Cyclopentylmethylether(CPME) havebeenemployedasgreen solvent Journal of Catalysis, 2014, 309,

9 Corso di Laurea Magistrale in Chimica e Tecnologia del armaco Corso di Laurea Magistrale in armacia Incontro per l orientamento alla tesi sperimentale Prof.ssa Daniela Lanari 22 ovembre 2017, Aula A via del Liceo Dipartimento di Science armaceutiche