Innovative Fluorination Methods & New Fluorinated Building Blocks For Life Science

Dr. Andreas Stolle Head of Business Line Pharma RSC Speciality Chemicals Symposium 2010-06-09

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Saltigo - A Global Player

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 2

Saltigo Key Facts & Figures

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 3

Saltigos Key Technology Areas

Chiral chemistry
Asymmetric hydrogenation, SMB chromatography, enzymes

Coupling reactions
Cross and aromatic C-hetero coupling

Challenging chemistry
Metal hydrides, high pressure, hydrogenation, phosgene, low temperature

Fluorine chemistry
HF, Halogen exchange reactions (Halex), PBSF

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 4

Fluorine Chemistry at Saltigo

Why are we working on Fluorine Chemistry ?
As many as 30-40% of agrochemicals and 20% of pharmaceuticals on the market are estimated to contain fluorine, including half of the top 10 drugs sold in 2005. Developmental pipelines are predicted to contain even more.
Chemical & Engineering News, 2006
O F CO2H N

F3C N N CH3

SO2NH2

Celecoxib (Celebrex, PFIZER) anti-inflammatory, 3.3 Bn$

high future potential of fluorine chemistry high future potential of fluorine chemistry
N

selective introduction of fluorine at the right position of a biologically active compound can lead to a significantly enhanced activity mild fluorination methods and suitable fluorinated building blocks permit an easy and elegant introduction of fluorine

Ciprofloxacin (Cipro, BAYER) antibiotic, 1.5 Bn$

H N

O
F3 C

CH3

Fluoxetine (Prozac, ELI LILLY) Fluoxetine(Prozac, ELI LILLY) antidepressant, 2.5 Bn$ antidepressant, 2.5 Bn$

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 5

What Makes Fluorine so Different ?

Effects of Fluorine in Drugs
Fluorine has a very small van der Waals Radius (1.35 A)
bioisoteric substitute of hydrogen (1.20 A) at an enzyme receptor site

Fluorine is the most electronegative element

affects acidity / basicity of neighboring groups induces a dipole moment increased rate of absorption & transport better binding to the enzyme

OH O HO OH O

OH O OH

F O

0,6 mg

H O

25 mg

Betamethasone
Dr. A. Stolle - Fluorine Chemistry at Saltigo

Cortisone
Slide 6

What Makes Fluorine so Different ?

Effects of Fluorine in Drugs
one fluorine is hydrophilic whereas more fluorines (CF3-, OCF3-, SCF3-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 activity reduced toxicity by metabolic stabilisation
O S

P450
HO

OH

S F3C

CF3

high oxidative stability

Ideal tool for organic synthesis in life science Ideal tool for organic synthesis in life science
Dr. A. Stolle - Fluorine Chemistry at Saltigo Slide 7

Selective Introduction of Fluorine in Aromatic Compounds

Nucleophilic Substitution Cl (Br) or NO2 F Ar-Cl(Br)
KF PTC; T KF PTC

Ar-F

Halex Reaction

Ar-NO2

Ar-F

Fluorodenitration
Activation by electron withdrawing groups in ortho and/or para-position

Diazotization of anilines and fluorination with HF or HBF4 Ar-NH2

NaNO2 HF

Ar-F

Schiemann Reaction

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 8

The Classical HALEX-Reaction

Anexate (Benzodiazepine-antagonist, Roche), Flumequine (antibacterial, 3M Sante / Sanofi), Sparticide (fungicide, Kumiai / Mitsubishi Chemicals), Castellan / Vista EWG EWG EWG (fungicide, AgrEvo), Action (herbicide, Kumiai / Novartis), Imidazenil (anxiolytic, Roche), Akuatim fluoride source (antibacterial, Otsuka), Sarafox (antibacterial, Abbott / Solvay), Serdolect (anxiolytic, Lundbeck), A-80556 n-1 [Cl,Br] (antibacterial, Abbott), n-1 [Cl,Br] Trovan IV catalyst, solvent (antibacterial, Pfizer), BMY-43748 (antibacterial, Bristol-Myers Squibb), BW-1555U88 T [Cl,Br]n F Cl(Br) (antidepressant, Wellcome Foundation), Ardent (herbicide, Diflufenican, May & F Baker), Aflogos (anti-inflammatory, Merck), E-5068 (antibacterial, Esteve), Diflucan (fungicide, Pfizer), PD-140248 (antibacterial, Warner Lambert), Sarafox (antibacterial, Abbott/Solvay), TAK-187 (Fungizid, Takeda), Ozex (antibacterial, Toyama), Trovan EWG= -NO2 (strong activation) (antibacterial, Pfizer), Clin-cher -CF3, CN, CHO, COCl COF Agrosciences), Femara (herbicide, Dow (medium activation) -Cl, Br (weak activation) (antineoplastic, Novartis), Myopathic (veterinary myopathic, Janssen Pharmaceutical), S-14280 (antithrombotic, Servier), YM-553 (antineoplastic, Yamanouchi), Moxifloxacin (antibacterial, Bayer), Flufenoxuron (Gemm/Sigona Bayer, Cascade American Cyanamid), Atabron/Helix (Ishihara Sangyo/Zeneca), Diflubenzuron (Vigilante Requirements for HALEX-reaction: Hoechst Roussel Vet, Dimilin Uniroyal/ Solvay Duphar, Micromite Uniroyal, Amilin Agrolex), Baroqueactivated substrate & high (Uniroyal temperature Virk (Yashima), Andalin reaction / Solvay Duphar), Teflubenzuron (Nomolt American Cyanamid / Mitsubishi Chemical, Dart Fertilizer of America), fluoride sources: KF, CsF, NaF Ciprofloxacin (antibacterial, Bayer), A-62824 (Abbott), A-80556 (Abbott), Clinafloxacin (Kyorin licensed dipolar aprotic solvent: sulfolane, DMF, NMP, to Warner-Lambert), CP-74667 (Pfizer), Advocin (Pfizer, vet.), Fandofloxacin (Dong Wha Pharma), PD-161314 (Warner Lambert) phase-transfer catalysts: e.g. Ph4PBr

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 9

The Ultimate Challenge in HALEX-Chemistry

Low Activated Substrates
N Cl
Cl N N Cl F

O O

Cl
F

F O N N

O O

KF / T Ph4PBr

F N N

Fluoxastrobin fungicide (BayerCropScience) 2005

HALEX-reaction fails for low activated substrates using HALEX-reaction fails for low activated substrates using traditional phase-transfer catalysts (e.g. Ph4PBr) traditional phase-transfer catalysts (e.g. Ph PBr)
4

Limitation in HALEXLimitation in HALEXchemistry chemistry

Cl

KF / T
Cl Cl

O N F F O

Ph4PBr

H N F

FR-145237 atherosclerosis (Fuhisawa Pharmaceuticals)

F

Cl

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 10

New Building Blocks Through Effective HALEX-Catalysts

SALTIGOs new generation of CNC-type HALEX-catalysts high activity at high temperature non-toxic & obtained by low-cost synthesis
Me2N Me2N + N Cl N N

CNC

enable the Halex-reaction of low & non-activated substrates and provide straightforward access to challenging fluorinated building blocks for life science.

CF3

F
17h, 205C 9 bar

chloro-arenes +
N N + N Cl

F
16h, 220C 6bar

NMe2 NMe2

F N N

F F
84%

F
48h, 220C 8bar

80%
48h, 220C 7bar

15h, 210C 12bar

F F F
69%

DE 102004033525 (Lanxess)

F
75%

F N

62%
Slide 11

Dr. A. Stolle - Fluorine Chemistry at Saltigo

2,2-Difluorobenzodioxoles as Building Blocks for Active Ingredients

2,2-Difluorobenzodioxoles Increased Lipophilicity
O H2 N O F F H2N O O

2,33 2,33

0,8
good mimic good mimic

Fungicides
F Cl NO2 Cl Cl Cl CN O O CN F

N H

N H

N H

Pyrrolnitril: natural product antifungal activity

Fenpiclonil lead compound launch in 1988

Fludioxonil (Celest) 8 x more active launch in 1993 (Ciba Geigy)

Slide 12

Dr. A. Stolle - Fluorine Chemistry at Saltigo

2,2-Difluorobenzodioxoles & Derivatives for Active Ingredients

Saltigo: HF-based manufacturing process
O O

established process established process

Cl2
O O Cl Cl

HF

O O

F F

DE 2819788 (Lanxess)

OH O O F F O O F F

Development of new drugs: Development of new drugs:

> 70 potential drug candidates > 70 potential drug candidates

H2N

O O

F F

COOH
O N H O O F F

HO2C

O O

F F

O2N Cl

O O

F F

O O

F F

~ 120 building blocks ~ 120 building blocks

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 13

Saltigos Fluorinating Reagent PBSF

Perfluoro-1-butanesulfonyl fluoride F F FF Colorless liquid O F3C S Low reactivity to moisture and air F Not ignitable F O F Protecting groups widely tolerated PBSF Used as precursor for flame retardants Produced at LANXESS in several metric tons per year

Scale-up Challenge: Racemization and price of reagents

PG R1 N R2
n

PG PBSF solvent, base fluoride R1 N R2

n

OH

Dr. 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 elevated temperature Appr. 80% overall yield Low levels of residual reagent and by-products

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 15

Successfull Scale-Up at 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-free fluorination

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 16

Why Outsource Fluorine Chemistry ?

Special Know How & Expertise required to succeed in fluorine 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 chemistry

Fluorine Chemistry will remain an experts field !! Fluorine Chemistry will remain an experts field

Dr. A. Stolle - Fluorine Chemistry at Saltigo

Slide 17

Dr. A. Stolle - Fluorine Chemistry at Saltigo