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Dr. A. Stolle - Fluorine Chemistry at Saltigo

Dr. Andreas StolleHead of Business Line Pharma

RSC Speciality Chemicals Symposium 2010-06-09

Innovative Fluorination Methods & New Fluorinated Building Blocks

For Life Science

Dr. A. Stolle - Fluorine Chemistry at Saltigo Slide 2

Saltigo - A Global Player


Saltigo Key Facts & Figures


Saltigo‘s Key Technology Areas

Chiral chemistry

Asymmetric hydrogenation, SMB chromatography, enzymes

Coupling reactions

Challenging chemistry

Fluorine chemistry

Cross and aromatic C-hetero coupling

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

HF, Halogen exchange reactions (Halex), PBSF


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

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

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$

F

NN

N

OCO2H

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

CH3

NN

SO2NH2

F3C

F3C

O NH

CH3

high future potential of fluorine chemistryhigh future potential of fluorine chemistry

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


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

O

OH

F

OH

OH

O

O

O

H

OH

OH

O

0,6 mg 25 mg

Betamethasone Cortisone


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

S S OHOH

O

SF3C

CF3

P450

high oxidative stability

Ideal tool for organic synthesis in life scienceIdeal tool for organic synthesis in life science


Selective Introduction of Fluorine in Aromatic Compounds

Nucleophilic Substitution Cl (Br) or NO2 → F

Diazotization of anilines and fluorination with HF or HBF4

KFAr-Cl(Br) Halex ReactionAr-F PTC; ∆T

KFAr-NO2 FluorodenitrationAr-F PTC

Activation by electron withdrawing groupsin ortho and/or para-position

Ar-NH2NaNO2

HFAr-F “Schiemann” Reaction


The Classical HALEX-Reaction

Anexate (Benzodiazepine-antagonist, Roche), Flumequine (antibacterial, 3M Sante /Sanofi), Sparticide (fungicide, Kumiai / Mitsubishi Chemicals), Castellan / Vista(fungicide, AgrEvo), Action (herbicide, Kumiai / Novartis), Imidazenil (anxiolytic,Roche), Akuatim (antibacterial, Otsuka), Sarafox (antibacterial, Abbott / Solvay),Serdolect (anxiolytic, Lundbeck), A-80556 (antibacterial, Abbott), Trovan IV(antibacterial, Pfizer), BMY-43748 (antibacterial, Bristol-Myers Squibb), BW-1555U88 (antidepressant, Wellcome Foundation), Ardent (herbicide, “Diflufenican”, May & 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 (antibacterial, Pfizer), Clin-cher (herbicide, Dow Agrosciences), Femara(antineoplastic, Novartis), Myopathic (veterinary myopathic, Janssen Pharmaceutical),S-14280 (antithrombotic, Servier), YM-553 (antineoplastic, Yamanouchi), Moxifloxacin (antibacterial, Bayer), Flufenoxuron (“Gemm”/”Sigona” Bayer, “Cascade” AmericanCyanamid), Atabron/Helix (Ishihara Sangyo/Zeneca), Diflubenzuron (“Vigilante” Hoechst Roussel Vet, “Dimilin” Uniroyal/ Solvay Duphar, “Micromite” Uniroyal, “Amilin”Agrolex), Baroque Virk (Yashima), Andalin (Uniroyal / Solvay Duphar), Teflubenzuron (“Nomolt” American Cyanamid / Mitsubishi Chemical, “Dart” Fertilizer of America),Ciprofloxacin (antibacterial, Bayer), A-62824 (Abbott), A-80556 (Abbott), Clinafloxacin (Kyorin licensed to Warner-Lambert), CP-74667 (Pfizer), Advocin (Pfizer, vet.), Fandofloxacin (Dong Wha Pharma), PD-161314 (Warner Lambert)

fluoride source

EWG EWG

Cl(Br)F

EWG

F

catalyst, solvent ∆T

[Cl,Br]n-1 [Cl,Br]n-1

[Cl,Br]n

-

-

Requirements for HALEX-reaction:

activated substrate & high reaction temperaturefluoride sources: KF, CsF, NaF…

dipolar aprotic solvent: sulfolane, DMF, NMP, …

phase-transfer catalysts: e.g. Ph4PBr

EWG= -NO2 (strong activation)-CF3, CN, CHO, COCl COF (medium activation)-Cl, Br (weak activation)


The Ultimate Challenge in HALEX-Chemistry Low Activated Substrates

N N

F FF

N N

O OFCl

NO O

ON

F F

F

F F

FNH

O

NO

Cl

N N

Cl ClCl

Cl Cl

Cl FR-145237 atherosclerosis

(FuhisawaPharmaceuticals)

Fluoxastrobinfungicide

(BayerCropScience) 2005Ph4PBr

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

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

KF / ∆T

Ph4PBr

KF / ∆T

Limitation in HALEX-chemistry

Limitation in HALEX-chemistry


New Building Blocks Through Effective HALEX-Catalysts

SALTIGO‘s new generation of CNC-type HALEX-catalysts

high activity at high temperaturenon-toxic & obtained by low-cost synthesis

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

CNC

NMe2N

Me2N N

N

Cl

+

DE 102004033525 (Lanxess)

N N

F FF

F

F F

CF3

FF

F

F

N

F F FF

F

N

NN

NMe2

NMe2

Cl

+

84%

75%

80%

62%

69%

16h, 220°C 6bar

17h, 205°C 9 bar

15h, 210°C 12bar

48h, 220°C 7bar

48h, 220°C 8bar

chloro-arenes+


2,2-Difluorobenzodioxoles as Building Blocks for Active Ingredients

2,2-Difluorobenzodioxoles – Increased Lipophilicity

O

O

FF

NH2O

O

NH2

π 2,33π 2,33 π 0,8

Fungicides

NH

OO

FF

CN

NH

CN

ClCl

NH

Cl

ClNO2

Pyrrolnitril:

natural product antifungal activity

Fenpiclonil

„lead compound“launch in 1988

Fludioxonil (Celest®)

8 x more active launch in 1993 (Ciba Geigy)

good mimicgood mimic


2,2-Difluorobenzodioxoles & Derivatives for Active Ingredients

Saltigo: HF-based manufacturing process

O

O

FF

O

O

O

O

ClCl

DE 2819788 (Lanxess)

established process established process

HFCl2

O

O

FF

COOH

O

O

FF

HO2C

O

O

FF

O

O

O

FF

OH

O

O F

F

NH2

O

O

FF

Cl

O2N

Development of new drugs:

> 70 potential drug candidates

Development of new drugs:

> 70 potential drug candidates

O

O

FF

O

NH

~ 120 building blocks ~ 120 building blocks


Saltigo‘s Fluorinating Reagent PBSF

Perfluoro-1-butanesulfonyl fluorideColorless liquidLow reactivity to moisture and air Not ignitableProtecting groups widely toleratedUsed as precursor for flame retardantsProduced at LANXESS in several metric tons per year

Scale-up Challenge: Racemization and price of reagents

SO

F3C

F F

F F

F F

OF

PBSF

NPG

OHn

NPG

Fn solvent, base

fluoride

R1 R2R1 R2 PBSF


Final Final ProcessProcess forfor ScaleScale--upup

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


SuccessfullSuccessfull ScaleScale--UpUp at at thethe 1000 L 1000 L ScaleScale

Run at multiple 100 kg -scale

Scale-up from 1 L to 1000 L

Robust process

All batches in spec.

Racemization-free fluorination


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 expert‘s field !Fluorine Chemistry will remain an expert‘s field !

Dr. A. Stolle - Fluorine Chemistry at Saltigo

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