Strategies for Accelerating the Development of Catalytic ...

Strategies for Accelerating the Development of Catalytic Enantioselective Reactions Hans-Ulrich Blaser, SOLVIAS AG, Basel Switzerland Singapore Catalysis Forum, 17. April 2008

Solvias A Technology Company 1970-1996

Central Research Center of Ciba-Geigy AG

1997

Scientific Services of Novartis AG

1 Oct.1999: Start as fully autonomous and independent technology company  Our Expertise

- Chemical, physical and biological analytics

- Synthesis with emphasis on (enantioselective) catalysis - Service related products (chiral ligands)

Outline



Background



Developing Enantioselective Processes



HTS at Solvias (Hydrogenation)



Conclusions

Chirality and Nature (Handedness)

Living organisms are chiral!! Normally, only one enantiomer is produced in Nature

biological material recognizes enantiomers

Chiral Aminoacids Image

Mirror image

CH 2 CONH 2

CH 2 CONH 2

C

C

H H 3N +

COO

-

-

S-aspargine bitter

H +NH 3

R-aspargine sweet

Enantiomers

Carmen Claver

OOC

It smells….

Carmen Claver

(R)-limonene orange

(S)-limonene lemon

Syntheses of Enantiomerically Pure Compounds (EPC) * Synthesis starting from naturally occurring chiral molecules (e.g. from fermentation) * Enantiomer separation

* Stoichiometric * Asymmetric Synthesis / Catalysis

Chiral chromatography Diastereomer separation Kinetic resolution

* Biocatalyst * Chemical catalyst

Enantioselective Catalysis Some Definitions: A Reminder enantioselective synthesis R1 R2

Y

+

X

R1

Z

R2

kinetic resolution

X Y-Z

+

R1 R2

preferred enantiomer

X

only possible in presence of a chiral auxiliary

Selectivity: Enantiomeric excess (ee, %(R) - %(S))

Y-Z

Chirality in Pharma Development AstraZeneca, GlaxoSmithKline, Pfizer (2006) Chirality Of the 128 molecules analyzed, 69 (54%) contained at least one stereogenic center. Of the 69 chiral molecules 67 were developed as single stereoisomers, with only two as racemates. J.S. Carey, D. Laffan, C. Thomson, M.T. Williams, Org. Biomol. Chem. 4 (2006) 2337

Importance of Chiral Compounds Market value for chiral fine chemicals (2000) Total Pharmaceutical application Other applications (agrochemicals, flavors etc)

6.6x109 $ 5.4x109 $ 1.2x109 $

Major user: Life Science Industry  Strong growth expected S.C. Stinson, Chemical & Engineering News, May 14, 2001, p. 45

Life Science Industry Product Development Process number of compounds

>50‘000 Lead Discovery

10 - 20

Lead Optimization

Activity Screening Models

1 -3 years

NCE‘s

Profiling Models

Process chemistry Toxicity Models

2 -3 years

1-3

Batch 0

Process / Formulation Dev.

Clinical / Field Tests

3 -4 years

Patent production of multi kg for tox and clinical tests  development of production process

1

Launch

Outline



Background



Developing Enantioselective Processes



HTS at Solvias (Hydrogenation)



Conclusions

Phases in Process Development 1. Choice of synthetic route: With or without catalysis? 2. Find effective catalytic system (ee; ton; tof) 3. Process optimization (catalytic step, overall synthesis) 4. Scale up, technical process 5. Manufacture (trouble shooting)

The (S)-Metolachlor Problem (Ciba-Geigy/Syngenta/Solvias)

MeO

O

Production process for racemate

metolachlor herbicide >30,000 t/y

CH2Cl

N

NH2 MeO MeO

O

NH OMe

MeO

O

CH2ClCOCl

CH2Cl

N

CH2Cl

N

O

Pt/C, H2SO4 50 °C, 5 bar

O OMe

+ NH2

+

CH2ClCOCl

?

R,1'R

S,1'R

the inactive stereoisomers MeO

MeO

O N

R,1'S

CH2Cl

O N

S,1'S

CH2Cl

the active stereoisomers

The (S)-Metolachlor Problem (Ciba-Geigy/Syngenta/Solvias)

MeO

O

Production process for enriched (S)-metolachlor MeO

10%

PXyl 2 Ph2P

Fe

N

s/c 2,000,000 reaction time ~3 h yield >99%, ee ~80%

CH2ClCOCl

NH

90%

S,1'R

MeO

O

Josiphos ligand Ir - Josiphos, acid + iodide 50°C, 80 bar

CH2Cl

the inactive stereoisomers

H

MeO

O N

CH2Cl

R,1'R

MeO

MeO

MeO

O N

metolachlor herbicide >30,000 t/y

CH2Cl

N

N

R,1'S

CH2Cl

O N

S,1'S

CH2Cl

the active stereoisomers

The History of rac-Metolachlor and (S)-Metolachlor 1970

Discovery of biological activity

1982

Bioactivity of (S) enantiomers detected

1978

Full-scale plant >20’000 t/y

1983

Route design: 4 variants  imine hydrogenation

1987

Ir - diphosphine (F. Spindler; J.A. Osborn)

1985 1993

1993/4 1995/6

Rh - cycphos (UBC Vancouver)

Ir - ferrocenyl diphosphine catalysts Patents of rac. metolachlor expired

Pilot results: e.e. 79%, ton 1’000’000, tof >200’000/h

16. Nov. 1996 First production batch

Some Lessons 1. Choice of synthetic route: With or without catalysis?

 Very situation dependent, not easy to accelerate

Important Factors when Deciding the Application of Catalysis Product

- availability of competitive alternative routes - time frame for development - cost vs added value

Catalytic reaction

- maturity

- known scope / limitations - catalyst availability - development time

- IP situation - required equipment / techniques - cost Chemist & Company

- education, acceptance of novel methods - catalytic know how and facilities

Some Lessons 2. Find effective catalytic system (ee; ton; tof) • Very often THE bottle neck • Highest potential for acceleration

Major hurdles  Availability of ligands (catalysts)  Testing equipment  Analytics

Some Lessons 3. Process optimization (catalytic step, overall synthesis) 4. Scale up, technical process 5. Manufacture (trouble shooting)  Less potential for acceleration Major hurdles

 Availability of ligands on technical scale / IP problems  Scale up equipment

Outline



Background



Developing Enantioselective Processes



HTS at Solvias (Hydrogenation)



Conclusions

Find Catalytic System (ee, ton, tof) • Choice of catalyst difficult due to high substrate specificity (analogies are often weak) • Requirements for catalyst performance for economical processes can be very demanding • Time constraints especially for new chemical entities in the pharma sector (less in agro)

Experience From Model Substrates e a s y s u b s tr a t e s

 -a c y l- d e h y d r o a m in o a c id d e riv a tiv e s ita c o n a t e s

g o o d s u b s tr a te s

 -a c y l-d e h y d ro a m in o a c id d e riv a t iv e s e n o l a c e ta te s

O R

a lly lic a c o h o l   -u n s a t u ra t e d a c id s

d iffic u lt s u b s t ra te s

 -fu n c tio n a liz e d k e to n e s

g o o d s u b s tr a te s

 -k e to e s te rs  -a m in o k e to n e s a r y l m e th y l k e to n e s

d iffic u lt s u b s tra te s

a lk y l k e to n e s

g o o d s u b s t ra t e s

s o m e N - a r y l im in e s s o m e c y c lic im in e s N -f u n c t io n a liz e d i m in e s

d iff ic u l t s u b s t ra t e s

s im p le a lk y l im in e s

R

O

O R O

Alk R' R '' R' R ''

Ar N R'

N

O

R

X

R '' Alkyl

X

NH, O, CH2

R

COOH, R

C H 2, O R ''

H,R O

O

R , O R e tc

R'

n o p r e fe r re d fu n c tio n a l g ro u p s t e tra s u b s titu te d a ro m a tic s (a lm o s t u n k n o w n )

e a s y s u b s tra te s

HO

R'

X

R '''

R'

C=C

R

X : C ,O ,N

N R,O H Alk

O Ar

C=O

A lk yl'

N

X

X: P=O N -C = O

R

N

C=N

Selected Customer Problems O

R

HetAr-OR

O

OR

N

Ar

X

NH N

O R

Ar

R

RO

R N

O

R R

O

R(CO) N

N N

R

R R R NR2

O

N

O HN

N

R

NR

OR

O

R

F

OH

O N

RC(O)

N

R N Ts

R

R O

Ar

R N

CO2R CO2R

RC(O)

N N

O

N C(O)R

N

O OH

HetAr R

N

NOBn

N

Ar

N OH

OH

Toolbox for Process Development

• Library of chiral ligands / metal precursors • Experimental setup for parallel testing • Suitable analytical procedures BUT MOST IMPORTANT: Optimal screening strategy

Selection of Chiral Ligands R2P

Fe

PR'2

PR2

PR'2

Fe

H

PAr2 PAr2

H

ferrocene based

R

P RR

P

R

P

O

P

P

P

phospholanes O O

monodentate

P N

X

PR'2

axially chiral / biaryl

O

O

PR2

X

MeO

P

P

Ph OMe

P-chiral R'2P

O PAr2 N

Ph

R

P-N ligands

N R'

PR2

Ph2P

various

PPh2

HT Screening Strategies Classical Strategy: Pre-existing library of ligands Solvias    

>600 chiral ligands (both enantiomers) 65% Solvias owned (mostly modular) ligand families 20% patented ligands of other suppliers 15% patent free ligands

DSM Strategy: Preparation and screening of “instant” monophos-type ligand libraries

Solvias Screening a Few Years Ago

series of 50 ml autoclaves 300 ml autoclave

The Solvias Octoclave

- 8 parallel runs with gaseous reactants - Very good mixing - Pressures up to 100 bar - Loading under inert conditions

Solvias HTS Today Symyx Based Platform • Capacity: 200 react. / day • Fully inert handling • Robotics for set-up

• 96-well plates, 0.4ml

• Up to 100bar (H2, CO)

• Robotics for analytics • (SFC, HPLC, GC)

SFC

Solvias HT Screening Strategy Design of Experiments (DoE) done by catalysis expert •

Combination of experience and serendipity

Ligands, additives, metals: Test large experimental space • •

Scouting experiments in 50 ml autoclave:  p, T HTS with s/c 25 (purity of substrate)

If ever possible: In situ catalyst generation

• Highest possible flexibility (metal, precursor type, ligand, counterion) HTS Analytics: Need for speed (rt 95%

P

Fe

P

H Me2 N

Mandyphos SL-M004-1



H

OMe

MeO

Ulrike Nettekoven (unpublished results)

OMe

P

Fe

Me2 N

metal conv.[%] ee[%]

MeOH, DCE, Toluene

Ph

MeO

Mandyphos SL-M004-1

Commercial ligand

[Ir(cod)Cl]2 100 87 (S)

OMe

Case: Hydrogenation of Acrylic Acid R

R'

COOH

H2 [cat*.]

R

R'

COOH

R = alkyl, R' = functionalized alkyl

Targets:

Delivered:

● >95% ee ● 3 kg product delivery within 3 months ● Commercially available ligand

98% ee s/c 1000, tof 250 h-1 3 kg product delivery within 5 weeks Commercial ligand (Solvias Portfolio)

Outline



Background



Developing Enantioselective Processes



HTS at Solvias (Hydrogenation)



Conclusions

Conclusions • Process development CAN be accelerated • Most potential: Screening phase • High throughput screening set-up very effective • Suitable screening strategy important • Essential: EXPERIENCED SCIENTISTS

Conclusions • HTS gives reproducible results • Larger experimental space explored (more leads, faster AND novel solutions) • Experience AND serendipity important • BUT: No replacement for classical experimentation

Conclusion  Scale up equipment

Acknowledgements Felix Spindler

Christoph Malan

Martin Kesselgruber Marc Thommen Benoit Pugin

Martin Studer Fred Naud

Hans Meier Collaborations

Ulrich Berens (Ciba SC) Stefan Geyser Walter Weissensteiner, University of Vienna Armin Börner, Likat Rostock Albrecht Salzer, RWTH Aachen

Andreas Pfaltz, University of Basel Antonio Togni, ETH Zürich Pher Andersson, University of Uppsala

Think catalytic!