MODERN CATALYSIS IN FINE CHEMICAL TRANSFORMATIONS

Technology, IP and Supply Chain Considerations

Paolo BraiucaProduct Manager – Catalysts

1

02

Emission

Control

Process

Technologies

Precious

Metal

Products

New

Business

Fine

Chemicals

Custom Pharma

Solutions

Controlled

Substances

APIs & Life Cycle

Management

Catalysts

High technology portfolio of Chemo and Biocatalysts products

Outstanding sustainable and efficient

manufacturing solutions

Market leading expertise

Global resources

• Heterogeneous

catalysts

• Homogeneous catalysts

• Chiral catalysts

• Biocatalysts and

Enzymes

• Ligands

HIGH TECHNOLOGY PORTFOLIO

4

HOM. HYDROG. Expiring IP

HOM. HYDROG.

Novel Technologies

COUPLING Innovation

COUPLING Commodities

HETCAT “Black Box”

BIOCATALYSIS Complex IP

Josiphos, Duphos,

Me-BIPHEP;

Noyori Tech.

Buchwald;

JM’s Pd Pi-Allyl.

Mostly IP free.

Buchwald ligands

commoditisation.

Great constant

“hidden”

innovation

Strong promises;

some great results; is

it under-delivering?Transfer hydrogenation;

Ester Hydrogenation; Novel

concepts (Baratta catalyst).

Innovation

IP Generation

Defend Profitability

Fund Innovation

Innovation

Competitiveness

Cost Reduction

Defend Profitability

Price reduction

Increased Utilisation

Commoditisation

IP Expiration

Where is the common ground?

Innovation. Cost. Benefit.

IP Protection

IP free solutions

Innovation Low cost

UniquenessBroad and

prompt availability

How can End Users and Technology Providers work together?

The Technology Provider Perspective

TEST ASSUMPTION

100 USD / kg Product

Catalyst Cost Contribution

10 USD/g Catalyst Price = 1% w/w loading

50 USD/g Catalyst Price = 0.2% w/w loading

150 USD/g Catalyst Price = 0.06% w/w loading

How to Achieve the Target

Complementary vs Competitive Technologies

Focus on the Solution not on the Technology

Short Term or Long Term Objective?

Can you decide a priori?

Noyori hydrogenation and transfer

hydrogenation catalysts and ADHs

Possible selectivity problems

with Noyori catalysts.

Biocatalysis stronger option.

Noyori catalysts good activity

but low stereoselectivity.

Biocatalysis stronger option.

First generation Noyori

catalysts (Ru-BINAP) or ADHs

Chemocatalysis

Catalyst screening

Reaction conditions screening

Custom catalyst development

Catalyst manufacturing development

Catalyst scale up

How to achieve the target

Biocatalysis

Enzyme screening

Reaction conditions screening

Enzyme engineering

Cloning/Expression host development

Fermentation development

Fermentation scale up

Application Process intensification

Application Process Scale up

Chemocatalysis

Limited number of catalysts

Broad set of reaction conditions

Optimise catalyst cost/price

How to achieve the target

Biocatalysis

Huge number of catalysts

Hardly the same catalyst for two processes

Significant range of reaction conditions

Optimise catalyst performance via enzyme engineering

Optimise enzyme production costs

Chemocatalysis

A complex technology with a

complex specialised

manufacturing

Metal management

Transportation, custom clearance

and duties

Role of the Supply Chain

Biocatalysis

A complex technology with a

(relatively) simple manufacturing

Delocalisation of the Fermentation

Role of local Toll Manufacturers

The importance of Trust

Two “Innovative Examples”

NEW PI-ALLYL PRECATALYSTS INSPIRATION

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Buchwald Palladacycles:

Advantages:

- Air / moisture stable

- Easily activated at or below rt

- Quantitative generation of L-Pd(0)

Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916

Issues:

- Scalability (1st Gen)

- Genotoxic carbazole generation (2nd, 3rd Gen)

- Limited ligand scope (1st, 2nd Gen)

carbazole

NEW PI-ALLYL PRECATALYSTS INSPIRATION

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JM SOLUTION: (L)Pd(π(π(π(π-allyl)Cl Complexes

Seechurn, C. C. C. J.; Parisel, S. L.; Colacot, T. J. J. Org. Chem. 2011, 76, 7918.

PHOSPHINE PI-ALLYL PALLADIUM CATALYSTS

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XPhosPd(crotyl)Cl

Pd-170

RuPhosPd(crotyl)Cl

Pd-171

[XantPhosPd(allyl)]Cl

Pd-177

[BrettPhosPd(crotyl)]OTf

Pd-173

CATALYST COMPARISON: 2°AMINATION

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PdH2N

L

OMs

PdH2N

L

ClPdH2N

L

Cl

RuPhos G1 RuPhos G2

RuPhos G3

Cy2P Oi-Pr

Oi-Pr

RuPhos (L)

a Corrected GC yields, b With 0.5 mol % additional RuPhos added. c 2.5 h.

entry catalyst conv (%)a

1 RuPhos G1 66

2 RuPhos G2 4

3 RuPhos G3 5

4 (RuPhos)Pd(allyl)Cl 80

5 (RuPhos)Pd(crotyl)Cl 87/97b/100b,c

6 (RuPhos)Pd(cinnamyl)Cl 95

7 RuPhos G1 / carbazole (0.5 mol%) 6

8 (RuPhos)Pd(crotyl)Cl + carbazole (0.5 mol%) 5

DeAngelis, A.J.; Gildner, P. G.; Chow, R.; Colacot, T. J. Org. Chem. 2015, 80, 6794

NEW PI-ALLYL Pd CATALYSTS IN ACTION!

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1°Amination 2°Amination Amidation

N

NC

OO

Bn

95%

Pd-175

Oxazolidinones

MeO

NH

S

N

85%

Pd-175

Aminothiazoles

N

92%

Pd-162

NC

NMe2

Cycloproplyamines

Indoles Sulfonamides

Alcohols

N N

MeO

OMe

O

94%Pd-170

Suzuki C-C α-Ketone Arylation

DeAngelis, A.J.; Gildner, P. G.; Chow, R.; Colacot, T. J. Org. Chem. 2015, 80, 6794

Gildner, P. G.; DeAngelis, A.J.; Colacot, T. J. Org. Lett. 2016, article in press

Ru Tethered Catalyst

Higher stability in the reaction conditions

Higher activity

Possible use in hydrogenation

‘Difficult’ substrates become possible targets

alfa-chloroacetophenone, polyfunctionalized molecules, propargyl ketones

NH2

NRu

Cl

Ts

NH

N

Ru

Cl

Ts

NPh

NH

Ph

S OO

C4-[(R,R)-teth-TsDpen RuCl]

Ru

Cl

C4-[(S,S)-teth-TsDpen RuCl]

C1-360

C1-350

NPh

NH

Ph

S OO

C3-[(R,R)-teth-MsDpen RuCl]

Ru

Cl

C3-[(S,S)-teth-MsDpen RuCl]

C1-311

C1-301

NPh

NH

Ph

S OO

C4-[(R,R)-teth-MsDpen RuCl]

Ru

Cl

C4-[(S,S)-teth-MsDpen RuCl]

C1-361

C1-351

NPh

NH

Ph

S OO

C3-[(R,R)-teth-TrisDpen RuCl]

Ru

Cl

C3-[(S,S)-teth-TrisDpen RuCl]

C1-318

C1-308

NPh

NH

Ph

S OO

C3-[(R,R)-teth-MtsDpen RuCl]

Ru

Cl

C3-[(S,S)-teth-MtsDpen RuCl]

C1-314

C1-304

NPh

NH

Ph

S OO

Ru

Cl

C4-[(R,R)-teth-TrisDpen RuCl]

C4-[(S,S)-teth-TrisDpen RuCl]

C1-368

C1-358

Wills et al. Organic Letters 2014, 16, 374; Wills et al. J. Org. Chem. 2013, 78, 8594.

Organic improvement on standard Noyori T.H.

Application to a very innovative

transformation disclosed by Merck

Mangion, Chen et al., Org. Lett. 2014, 16, 2310.

Novel Applications

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COMPLEX CHEMISTRY.SIMPLY DELIVERED.

www.jmfinechemicals.com