PPT template: SALTIGO - Chemspec Events

Saltigo - A Global PlayerDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 2

Saltigo‘s Key Technology AreasChiral chemistryAsymmetric hydrogenation, SMB chromatography, enzymesCoupling reactionsCross and aromatic C-hetero couplingChallenging chemistryMetal hydrides, high pressure, hydrogenation, phosgene,low temperatureFluorine chemistryHF, Halogen exchange reactions (Halex), PBSFDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 4

Fluorine Chemistry at SaltigoWhy are we working on Fluorine Chemistry ?„As many as 30-40% of agrochemicals and 20% ofpharmaceuticals on the market are estimated to containfluorine, including half of the top 10 drugs sold in 2005.Developmental pipelines are predicted to contain evenmore.“Chemical & Engineering News, 2006F 3CNNSO 2NH 2FOCH 3Celecoxib (Celebrex®, PFIZER)anti-inflammatory, 3.3 Bn$CO 2H high future potential of of fluorine chemistryNNNselective introduction of fluorine at the right position of abiologically active compound can lead to a significantlyenhanced activityCiprofloxacin (Cipro®, BAYER)antibiotic, 1.5 Bn$O N H CH 3mild fluorination methods and suitable fluorinated buildingblocks permit an easy and elegant introduction of fluorineF 3CFluoxetine (Prozac®, (Prozac, ELI LILLY)antidepressant, 2.52.5Bn$Bn$Dr. A. Stolle - Fluorine Chemistry at Saltigo Slide 5

What Makes Fluorine so Different ?Effects of Fluorine in Drugs• one fluorine is hydrophilic whereas more fluorines (CF 3 -, OCF 3 -, SCF 3 -group)are strongly lipophilic→increased lipophilicity⇒ improved bioavailability & pharmacological activity• strength of the C-F bond exceeds that of the C-H bond→ increased oxidative stability against enzymatic attack⇒⇒higher and broader range of activityreduced toxicity by metabolic stabilisationOS P450S OHHOF 3CSCF 3high oxidative stabilityIdeal tool for fororganic synthesis in in life life scienceDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 7

Selective Introduction of Fluorine inAromatic CompoundsNucleophilic Substitution Cl (Br) or NO 2→ FAr-Cl(Br)KFPTC; ∆TAr-FHalex ReactionAr-NO 2KFPTCAr-FFluorodenitrationActivation by electron withdrawing groupsin ortho and/or para-positionDiazotization of anilines and fluorination with HF or HBF 4Ar-NH 2NaNO 2HFAr-F“Schiemann” ReactionDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 8

The Ultimate Challenge in HALEX-ChemistryLow Activated SubstratesNOClNClNClKF / ∆TPh 4 PBrFNFNFClONFNOONOFluoxastrobinfungicide(BayerCropScience)2005HALEX-reaction fails fails for for low low activated substrates usingtraditional phase-transfer catalysts (e.g. Ph Ph 4 PBr) 4 Limitation in in HALEXchemistryClClClKF / ∆TPh 4 PBrFFFONOHNFFFFR-145237atherosclerosis(FuhisawaPharmaceuticals)ClDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 10

New Building Blocks Through EffectiveHALEX-CatalystsSALTIGO‘s new generation of CNC-type HALEX-catalysts• high activity at high temperature• non-toxic & obtained by low-cost synthesisMe 2NMe 2N+NClCNCNN…enable the Halex-reaction of low & non-activated substrates and provide straightforwardaccess to challenging fluorinated building blocks for life science.F84%CF 3FFFF17h, 205°C9 bar48h, 220°C8barchloro-arenes+N + NMe 2NNCl NMe 215h, 210°C12bar16h, 220°C6bar48h, 220°C7barFNFFNF80%DE 102004033525(Lanxess)F FF FF69%F75%N 62%Dr. A. Stolle - Fluorine Chemistry at Saltigo Slide 11

2,2-Difluorobenzodioxoles as BuildingBlocks for Active Ingredients2,2-Difluorobenzodioxoles – Increased LipophilicityOFON H 2OFH 2NOπ 2,33 π 0,8Fungicidesgood mimicClNO 2ClClClCNOFOFCNPyrrolnitril:NHnatural productantifungal activityFenpiclonilNH„lead compound“launch in 1988NHFludioxonil (Celest®)8 x more activelaunch in 1993(Ciba Geigy)Dr. A. Stolle - Fluorine Chemistry at Saltigo Slide 12

2,2-Difluorobenzodioxoles & Derivativesfor Active IngredientsSaltigo: HF-based manufacturing processOCl 2OClHFOFestablished processOOClOFDE 2819788 (Lanxess)Development of of new drugs:> 70 70 potential drug drug candidatesN H 2OOFFOOOFFOHOOFFNHOOOFFHO 2COOFFO 2NClOOFFCOOHOOFF~ 120 building blocksDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 13

Saltigo‘s Fluorinating Reagent PBSFPerfluoro-1-butanesulfonyl fluorideF• Colorless liquid• Low reactivity to moisture and airF 3C• Not ignitable• Protecting groups widely tolerated• Used as precursor for flame retardants• Produced at LANXESS in several metric tons per yearF F FF FPBSFS OO FScale-up Challenge: Racemization and price of reagentsPGR 1N R 2 PBSFPGR 1N R 2nOHsolvent, basefluoridenFDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 14

Final Process for Scale-up Solvent toluene 1.25 eq. fluorinating agent 0.5 eq. additional fluoride Reaction at slightly elevatedtemperature Appr. 80% overall yield Low levels of residual reagentand by-productsDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 15

Successfull Scale-Upat the 1000 L Scale Run at multiple 100 kg -scale Scale-up from 1 L to 1000 L Robust process All batches in spec. Racemization-freefluorinationDr. A. Stolle - Fluorine Chemistry at Saltigo Slide 16

Why Outsource Fluorine Chemistry ?Special Know How & Expertise required to succeed influorine chemistry• Safe handling of toxic & corrosive reagents(e.g. HF, BF3, DAST, …)• Special apparatus & technical equipment (PTFE, hastelloy, …)• Properties of fluoro compounds (stability, reactivity, toxicity)• Fluorination methods• Building blocks & commercial intermediates• Saltigo has more than 45 years of expertise in fluorine chemistryFluorine Chemistry will remain an expert‘s field !!Dr. A. Stolle - Fluorine Chemistry at Saltigo Slide 17

Dr. A. Stolle - Fluorine Chemistry at Saltigo