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

S-asparginebitter

R-asparginesweet

+

C-OOC

NH3

H

CH2CONH2

+

CCOO-

H3NH

CH2CONH2

Enantiomers

Chiral Aminoacids

Carmen Claver

Mirror imageImage

(R)-limonene (S)-limoneneorangeorange lemon

It smells�.

Carmen Claver

* Synthesis starting from naturally occurring chiral molecules (e.g. from fermentation) Chiral chromatography * Enantiomer separation Diastereomer separation Kinetic resolution

Syntheses of Enantiomerically Pure Compounds (EPC)

* Stoichiometric * Asymmetric Synthesis / * Biocatalyst Catalysis * Chemical catalyst

Enantioselective CatalysisSome Definitions: A Reminder

YR1

R2

X Z Y-ZR1

R2

XY-Z

R1

R2 X+ +

preferredenantiomer

enantioselective synthesis

kinetic resolution

only possible in presence of a chiral auxiliarySelectivity: Enantiomeric excess (ee, %(R) - %(S))

Chirality in Pharma DevelopmentAstraZeneca, 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 6.6x109 $Pharmaceutical application 5.4x109 $Other applications (agrochemicals, flavors etc) 1.2x109 $

Major user: Life Science Industry

Strong growth expected

S.C. Stinson, Chemical & Engineering News, May 14, 2001, p. 45

Life Science IndustryProduct Development Process

PatentPatent

Lead Discovery

Lead Optimization NCE�s

Activity ScreeningModels

Batch 0

Clinical / Field Tests

Process / FormulationDev.

ProfilingModels

ToxicityModels

Launch

1 -3 years 3 -4 years

Processchemistry

>50�000 10 - 20 1 - 3 1

number of compounds

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

2 -3 years

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)

N CH2Cl

OMeO

N CH2Cl

OMeO

N

O

CH2Cl

MeO

N CH2Cl

OMeO

N CH2Cl

OMeO

R,1'R S,1'Rthe inactive stereoisomers

metolachlorherbicide

>30,000 t/y

R,1'S S,1'S

the active stereoisomers

?O

OMe

NH2

CH2ClCOCl

+

+

Production process for racemate

OOMe

NH

MeO

NH2

Pt/C, H2SO4

50 °C, 5 bar

CH2ClCOCl

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

N CH2Cl

OMeO

N CH2Cl

OMeO

N

O

CH2Cl

MeO

N CH2Cl

OMeO

N CH2Cl

OMeO

R,1'R S,1'Rthe inactive stereoisomers

metolachlorherbicide

>30,000 t/y

R,1'S S,1'S

the active stereoisomers

N

MeO

PXyl2

HPh2P

NH

MeO

Fe

Josiphos ligand

Ir - Josiphos, acid + iodide50°C, 80 bar

s/c 2,000,000reaction time ~3 h

yield >99%, ee ~80%

Production process for enriched (S)-metolachlor

CH2ClCOCl

90%

10%

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

1970 Discovery of biological activity

1978 Full-scale plant >20�000 t/y

1982 Bioactivity of (S) enantiomers detected

1983 Route design: 4 variants imine hydrogenation

1985 Rh - cycphos (UBC Vancouver)

1987 Ir - diphosphine (F. Spindler; J.A. Osborn)

1993 Ir - ferrocenyl diphosphine catalysts

1993/4 Patents of rac. metolachlor expired

1995/6 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 & - education, acceptance of novel methodsCompany - catalytic know how and facilities

2. Find effective catalytic system (ee; ton; tof)

Some Lessons

� Very often THE bottle neck

� Highest potential for acceleration

Major hurdles

Availability of ligands (catalysts)

Testing equipment

Analytics

3. Process optimization (catalytic step, overall synthesis)

4. Scale up, technical process

5. Manufacture (trouble shooting)

Some Lessons

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

NR '

R ''

A r

NR '

R ''

X N

R

NR '

R ''

A l kyl

X : P = O N -C = O C = N

s o m e N -a ry l im in e ss o m e c yc lic im in e sN -fu n c tio n a liz e d im in e s

g o o d s u b s tra te s

d iff ic u l t s u b s tra te s s im p le a lk y l im in e s

H,R

R''

R '''

R '

X

RR

R'O

COH

H 2 , O

RR'

C = C

e a s y s u b s tra te s -a c yl-d e h yd ro a m in o a c id d e riv a tive sita c o n a te s

-a c yl-d e h yd ro a m in o a c id d e riva t iv e se n o l a c e ta te s

N H , O , C H 2

g o o d s u b s tra te s

a lly lic a c o h o l -u n s a tu ra te d a c id s

C O O H , R

R , O R e tc

d iffic u lt s u b s tra te s n o p re fe rre d fu n c tio n a l g ro u p ste tra s u b s titu te da ro m a tic s (a lm o s t u n k n o w n )

O

Alk Ar

R X

O O

X

O

O

R N R,O HO

RO

Alk Alkyl'

X : C ,O ,N

C =Oea sy s u b s tra tes -fu n ctio n a lize d ke to n e s

-ke to es te rs -am in o ke to n e saryl m eth yl ke to n es

g o o d s u b s tra te s

d ifficu lt su b stra tes a lk yl k e to n es

Selected Customer Problems

O

Ar

R R Ar

NHN

R O HetAr-OR

R

N O

NH

O

R

RR

R

O

OR

N

N

R

RO

NO

X

Ar

NRC(O)

NR

ON

RR

N

RO

CO2R

CO2R

N

NR2

Ts

F

N

NNR

NOBnRN

OH

O

Ar

RC(O)

C(O)R

O

NR

R

N

O

NOH

N

R

ORO

R(CO)

N

NOH

OHHetAr

Toolbox for Process Development

� Library of chiral ligands / metal precursors

� Suitable analytical procedures

BUT MOST IMPORTANT: Optimal screening strategy

� Experimental setup for parallel testing

Selection of Chiral Ligands

PAr2PAr2

PR

R

PR

R

XX

PR2

PR'2

PR'2

HR2P

PPPhPh

MeO OMe

N

O

PAr2

R

O

OP N

P P

OO O

P

P

PR'2

H

PR2

N

R'2P

PR2R' PPh2Ph2P

axially chiral / biaryl

phospholanes

ferrocene based

Fe

P-chiral

P-N ligandsmonodentate

Fe

various

HT Screening Strategies

Classical Strategy: Pre-existing library of ligands

DSM Strategy: Preparation and screening of

�instant� monophos-type ligand libraries

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

Solvias Screening a Few Years Ago

300 ml autoclave

series of 50 ml autoclaves

The Solvias Octoclave

- Pressures up to 100 bar

- 8 parallel runs with gaseous reactants- Very good mixing

- Loading under inert conditions

Solvias HTS TodaySymyx Based Platform

SFC

� 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)

Design of Experiments (DoE) done by catalysis expert

� Combination of experience and serendipity

If ever possible: In situ catalyst generation

� Highest possible flexibility (metal, precursor type, ligand, counterion)

HTS Analytics: Need for speed (rt << 15 min / sample required)

� SFC, GC, fast HPLC

Ligands, additives, metals: Test large experimental space

� Scouting experiments in 50 ml autoclave: p, T

� HTS with s/c 25 (purity of substrate)

Solvias HT Screening Strategy

Screening Work-Flow

DESIGNDifferent ligand classes (Key-, High Priority- and Low Priority Ligands)Different metal precursors and ratios, different additives, different solvents

Definition of Ligand Definition of Reaction

Screening Work-Flow

97.41

Case: Hydrogenation of Acrylic Acid

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

State of the Art: Up to 90% eeSeveral Cat.-systems described Mainly Rh-systems known (expensive metal!)

Rh-based catalyst systems at low to mediumpressure expected to work best

H2R

R'

COOH

R'R COOH

[cat*.]

R = alkyl, R' = functionalized alkyl

Design and Results of 1st HTS plateRational Design Based on Experience

HT Screening: �In situ mixing�, s/c: 25; 1 bar, 25°C, 1h

*Ligand

metal conv.[%]ee[%]

Hit 1

[Rh(nbd)2]BF410092

PPFe

Kephos SL-P053-2

Hit 2

[Rh(nbd)2]BF410090

P

N

P

O

O

Fe

SL-F056-1

Felix Spindler (unpublished results)

[Rh(nbd)2]BF4 in situand 3 [Rh(PP)cod]BF4

13 Ligands (Josi-, Ke-Tania-, Wal-, Mandy-,

Fengphos, DIPAMP)MeOH

NEt3

DMAP

ee <95% experimental ligands

Design and Results of 2nd HTS plate"Serendipity added" Design

Hit 1: in MeOH

[RuI2(p-cymene)]2100

>98 (R)

PH

Me2N

OMe

OMe

Ph

PH

MeO

MeO

PhMe2N

Fe

Mandyphos SL-M004-1

*Ligand

metal conv.[%]ee[%]

Hit 2: in EtOH/DCE = 2/1

87 (S)

[Ir(cod)Cl]2100

PH

Me2N

OMe

OMe

Ph

PH

MeO

MeO

PhMe2N

Fe

Mandyphos SL-M004-1

Ulrike Nettekoven (unpublished results)

[Rh(nbd)2]BF4, [(Rh(cod)Cl]2, [Ir(cod)Cl]2

[Ru(p-cymene)l2]2

27 Ligands (10 Fengphos, 6 Kephos, Tania-, Wal-, Mandy-,

Josiphos, BINAP, bppm)

MeOH,DCE,

Toluene

HT Screening: �In situ mixing�, s/c: 25; 10 bar, 40 °C, 15 h

ee >95% Commercial ligand

Case: Hydrogenation of Acrylic Acid

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

Delivered: 98% ees/c 1000, tof 250 h-1

3 kg product delivery within 5 weeksCommercial ligand (Solvias Portfolio)

H2RR'

COOH

R'R COOH

[cat*.]

R = alkyl, R' = functionalized alkyl

Outline

Background

Developing Enantioselective Processes

HTS at Solvias (Hydrogenation)

Conclusions

Conclusions

� Suitable screening strategy important

� Process development CAN be accelerated

� Most potential: Screening phase

� High throughput screening set-up very effective

� Essential: EXPERIENCED SCIENTISTS

Conclusions

� BUT: No replacement for classical experimentation

� HTS gives reproducible results

� Larger experimental space explored (more leads, faster AND novel solutions)

� Experience AND serendipity important

Conclusion

Scale up equipment

Acknowledgements

Felix SpindlerChristoph MalanMartin KesselgruberMarc Thommen Benoit PuginMartin StuderFred NaudHans Meier

CollaborationsUlrich Berens (Ciba SC)Stefan Geyser

Walter Weissensteiner, University of Vienna Andreas Pfaltz, University of Basel Armin Börner, Likat Rostock Antonio Togni, ETH ZürichAlbrecht Salzer, RWTH Aachen Pher Andersson, University of Uppsala

Think catalytic!