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2016

Metathesis Applications in API SynthesisOctober 18th, 2016

2

AGENDA

MATERIA

Materia’s Catalyst Business Model

Metathesis and Applications

Maximizing Reaction Efficiency

Macrocyclizations on Scale

Capabilities, Services, and Support

3

MATERIA’S BUSINESS MODEL

MATERIA

1. Catalyst Sales• IP included in purchase price

• No license fees or royalties

• No restrictions on patenting API composition or route

• Transferable to 3rd party CMO/CRO

2. Technical Services• Process guidance (free)

• Catalyst screening

• Catalyst development

• Process development and optimization

• Intermediate synthesis (non-GMP)

…our mission is to accelerate Grubbs’ catalyst use in the pharmaceutical industry

Metathesis and Applications

5

PRIMARY OLEFIN METATHESIS REACTIONS

MATERIAMetathesis mechanism: Sanford, M. S.; Love, J. L.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543.

Ring-Closing Metathesis (RCM): makes ring structures

Cross Metathesis (CM): creates new olefins (large or small molecules)

Ring-Opening Metathesis Polymerization (ROMP): makes polymers

MATERIA6

Subsea Insulation

Chlorinated

Fluid HandlingDownhole Tools

• Commercial

Electronic

Materials

• Developmental

Subsea Buoyancy

• Commercial

Lightweight

Pressure Vessels

• Developmental

Auto Composites

• Developmental

POLYMER APPLICATIONS: ADVANCED MATERIALS

MATERIA

CHEMICAL APPLICATIONS: BIORENEWABLES

7

Natural

Oil

Specialty

Chemicals

Olefins

Oleochemicals

Grubbs

Catalyst®

1-butene

Metathesis

• Flexible feedstock process (palm, soy, rapeseed, canola, etc.)

• Elevance was spun off as a JV between Cargill and Materia

• Announced over 1.9 billion lbs+ / year of bio refinery capacity

• Commercial-scale natural feedstock available for new product

development and mass production using Grubbs Catalyst®

based metathesis

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PHARMA APPLICATIONS: MACROCYCLES

MATERIA

SimeprevirHCV NS3-4A Protease Inhibitor

Carbon-carbon bonds formed by olefin metathesis

CiluprevirHCV NS3-4A Protease Inhibitor

Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Yee, N. K.; Senanayake, C. H. Org. Proc. Res. Dev. 2009, 13, 250.

Horvath, A. et al (Janssen Pharmaceuticals, Inc., USA). Improved

process for preparing an intermediate of the macrocyclic protease

inhibitor TMC 435. PCT Int. Appl. 2013061285, May 2, 2013.

9

WHY MACROCYCLES?

MATERIA

General reviews:

Giordanetto, F.; Kihlberg, J. J. Med. Chem. 2014, 57, 278.

Villar, E. A.; Beglov, D.; Chennamadhavuni, S.; Porco Jr., J. A.; Kozakov, D.;

Vajda, S.; Whitty, A. Nature Chemical Biology, 2014, 10, 723.

Potential to Hit “Undruggable” Targets

• May replace larger molecules (e.g. biologics) for difficult targets1

• Large, saturated ring balances preorganization with flexibility2

Oral Bioavailabity Beyond Rule of 5 (bRo5) Space

• Better diffusion across membranes in studies of matched acyclic/macrocyclic pairs (both peptide and non-peptide)3

• “Chameleon-like behavior” - exposed polar surface area in aqueous media, conformational changes (e.g. internal H-bonding) enable membrane permeability4

Unexplored Intellectual Property Space

• Tying ends of pharmacophore into a macrocycle may lead to new, patentable composition

1. Espada, A.; Broughton, H.; Jones, S.; Chalmers, M. J.; Dodge, J. A. J. Med. Chem. 2016, 59, 2255.

2. Mallinson, J.; Collins, I. Future Med. Chem. 2012, 4, 1409.

3. Bogdan, A. R.; Davies, N. L.; James, K. Org. Biomol. Chem. 2011, 9, 7727.

4. Whitty, A.; Zhong, M.; Viarengo, L.; Beglov, D.; Hall, D. R.; Vajda, S. Drug Discovery Today, 2016, 21, 712.

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PHARMA APPLICATIONS: STAPLED PEPTIDES

MATERIA

Metathesis-enabled peptide staples hold peptides

in helical conformation to enhance stability and

cell penetration while maintaining specificity.

Drug PropertiesSmall

MoleculesBiologics Peptides

Stapled

Peptides

Cell Penetration ++ -- -- ++

Specificity + ++ ++ ++

Stability ++ ++ -- ++

1. Drahl, C. C&E News vol. 86, no. 22. pp.18-23 (June 2, 2008).

2. http://aileronrx.com/science_stapled-peptide-technology.php

3. Image: Kim, Y.-W.; Grossman, T. N.; Verdine, G. L. Nature Protocols 2011, 6, 761.

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PHARMA APPLICATIONS: OTHER SP3-RICH STRUCTURES

MATERIA

Saturated N-Heterocyclic Cathepsin K Inhibitor

Spirocyclic NK-1 Receptor Antagonist

Carbon-carbon bonds formed by olefin metathesis

Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M. Jr. Org. Process Res. Dev. 2008, 12, 226.

Wu, G. G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J. Sprague, V.

M.; Castellanos, L. P.; Chen, Y.; Piorier, M.; Mergelsberg, I. (Schering-

Plough, USA) WO2010028232, 2010

Maximizing Reaction Efficiency

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CATALYST SELECTION

MATERIA

General RCM

C848

Grubbs II

C627

Hoveyda-Grubbs II

C949

Nolan-Grubbs II

RCM to Trisubstituted

C571 C711 C633

CM to Trisubstituted Z-selective (CM or RCM)

General CM

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GENERAL PURPOSE CATALYSTS IN ACTION

MATERIA

C627

Hoveyda-Grubbs II

C848

Grubbs II

1. Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M. Jr. Org. Proc. Res. Dev. 2008, 12, 226.

2. Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S. N.; Ouyang, X.; Clark, W. M. Jr. Tetrahedron 2009, 65, 6291.

3. Wang, G.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 8088.

Cross Metathesis3

Ring-Closing Metathesis1,2

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STERIC SPECIALIST CATALYSTS IN ACTION

MATERIA

Cross Metathesis2

1. Allen, C. E.; Chow, C. L.; Caldwell, J. J.; Westwood, I. M.; van Montfort, R. L. M.;

Collins, I. Bioorg. Med. Chem. 2013, 21, 5707

2. Stewart, I. C.; Douglas, C. D.; Grubbs, R. H. Org. Lett. 2008, 10, 441.

Ring-Closing Metathesis1

C823 (Grubbs I):

C627 (Hoveyda-Grubbs II):

C571:

0%

0%

82%

C571

C711

C571:

C627 (Hoveyda-Grubbs II):

C711:

60%

78%

98%

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Z-SELECTIVE CATALYST IN ACTION

MATERIA

Cross Metathesis2

1. Mangold, S. L.; Grubbs, R. H. Chem. Sci. 2015, 6, 4561.

2. Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H. Angew. Chem.

Int. Ed. 2013, 52, 310.

Ring-Closing Metathesis1

C633

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TEMPERATURE AND CONCENTRATION

MATERIA

Ring-Closing Metathesis

Temperature (°C) Concentration (M)Heat Necessary?

No, unless there is ring strain

No, unless there is ring strain

Possibly, if there is an

entropic barrier

Yes, entropic barrier and high

dilution are likely

Yes, to overcome sterics

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TEMPERATURE AND CONCENTRATION

MATERIA

Cross Metathesis

Temperature (°C) Concentration (M)Heat Necessary?

No, Type I CM is fast

Yes, electron deficient

olefins are slow to react

Yes, to overcome sterics

No, selectivity may suffer at

higher temperature

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SOLVENT SELECTION

MATERIAhttp://allthingsmetathesis.com/solvent-considerations-in-ruthenium-catalyzed-metathesis-reactions

Preferred Solvents

(non-coordinating)

Tolerated Solvents

(coordinating/nucleophilic)

Avoid if Possible

(strongly coordinating)

hexane, heptane MeOH, EtOH, i-PrOH MeCN

toluene, xylene Acetone, HOAc DMSO, DMF, NMP

TBME, 2-MeTHF Et2O, THF Pyridine and other amines

DCM, DCE, PhCl water (neutral/acidic) water (basic)

EtOAc, i-PrOAc

Perfluoroalkanes

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WATCH FOR SOLVENT IMPURITIES

MATERIANicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005, 9, 513.

Inconsistent results on scale-up

− Catalyst deactivation

− Olefin isomerization

− Epimerization of vinylcyclopropane

Identified morpholine as an impurity in toluene (<20 ppm)

− [morpholine] ~ [catalyst]

Purification of toluene led to consistent results

21

COORDINATING GROUPS: ADD ACID

MATERIAWilliam, A. D.; Lee, A. C.-H. Chimia, 2015, 69, 142.

Catalyst (10 mol%) Additive, Time Yield (trans:cis)

C823 (Grubbs I) None, 16h n.d.

C848 (Grubbs II) None, 16h n.d.

C823 (Grubbs I) 5 equiv HCl in MeOH, 16h 10 %, 86:14

C848 (Grubbs II) 5 equiv HCl in MeOH, 4h 70 %, 94:6

C823 (Grubbs I) 5 equiv TFA in MeOH, 16h 8 %, 85:15

C848 (Grubbs II) 5 equiv TFA in MeOH, 4h 86 %, 94:6

Potential

ligands

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COORDINATING GROUPS: START WITH THE SALT

MATERIA

Wu, G. G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J. Sprague, V. M.;

Castellanos, L. P.; Chen, Y.; Piorier, M.; Mergelsberg, I. (Schering-Plough, USA)

WO 2010028232, March 11, 2010

Varubi®(rolapitant) FDA-approved September 2015 for treatment of chemotherapy-induced nausea and vomiting)

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OLEFIN ISOMERIZATION

MATERIA

Vaniprevir RCM

Kong, J.; Chen, C-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey,

J.; Li, H.; Zacuto, M. J. J. Org. Chem. 2012, 77, 3820.

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OLEFIN ISOMERIZATION - HYPOTHESES

MATERIA

1. http://allthingsmetathesis.com/inhibiting-olefin-isomerization/

2. Ru-H formation: Dinger, M. B. Mol, J. C. Eur. J. Inorg. Chem. 2003, 15, 2827.

3. Ru-H isomerization (in)activity: Higman, C. S.; Plais, L.; Fogg, D. E.

ChemCatChem 2013, 5, 3548.

4. RuNPs: Higman, C. S.; Lanterna, A. E.; Marin, M. L.; Sciano, J. C.; Fogg, D. E.

ChemCatChem 2016, 8, 2426.

Hydride Formation Nanoparticles

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OLEFIN ISOMERIZATION - PREVENTION

MATERIAHong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005,

127, 17160.

C848

Grubbs II

Additive Equiv A B

none - <5% >95%

AcOH 0.1 >95% none

benzoquinone 0.1 >95% none

galvinoxyl 0.2 80% 20%

TEMPO 0.5 7% 93%

4-methoxyphenol 0.5 17% 83%

BHT 0.5 4% 93%

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CATALYST STABILITY - INERT CONDITIONS

MATERIA

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120 140 160 180 200

cata

lyst

rem

ain

ing

(%)

time (h)

Decomposition of C627, C848, C827, & C949

% C627 (C6D6)

% C627 (CD2Cl2)

% C627 (CDCl3)

% C627 (C6D6 wet)

% C827 (C6D6)

% C827 (CD2Cl2)

% C827 (CDCl3)

% C827 (C6D6 wet)

% C848 (C6D6)

% C848 (CD2Cl2)

% C848 (CDCl3)

% C848 (C6D6 wet)

% C949 (C6D6)

% C949 (CD2Cl2)

% C949 (CDCl3)

% C949 (C6D6 wet)

C627

C949

C827

C848

Adam Johns

• Catalyst solutions were prepared

with rigorous exclusion of oxygen

and moisture (samples were

prepared in the glovebox using

freshly distilled and/or degassed

NMR solvent).

• 0.02 M catalyst in NMR solvent

with internal standard

• Wet Benzene contained 0.035 M

H2O1

• NMR samples were stored on

bench top at room temp in the

dark over the 8 days.

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120 140 160 180

cata

lyst

rem

ain

ing

(%)

time (h)

Decomposition of C627, C827, C848 & C949 (Air)

% C627 (C6D6)

% C627 (CD2Cl2)

% C627 (CDCl3)

% C627 (C6D6 wet)

% C827 (C6D6)

% C827 (CD2Cl2)

% C827 (CDCl3)

% C827 (C6D6 wet)

% C848 (C6D6)

% C848 (CD2Cl2)

% C848 (CDCl3)

% C848 (C6D6 wet)

% C949 (C6D6)

% C949 (CD2Cl2)

% C949 (CDCl3)

% C949 (C6D6 wet)

27

CATALYST STABILITY - NON-INERT CONDITIONS

MATERIA

C627

C949

C827

C848

Adam Johns

• Catalyst solutions were prepared

by sparging with oxygen, no

attempt to keep moisture out of

the samples. (Samples were

prepared outside of the glovebox,

on the lab bench top with NMR

solvents used as is).

• 0.02 M catalyst in NMR solvent

with internal standard

• Wet Benzene contained 0.035 M

H2O1

• NMR samples were stored on

bench top at room temp in the

dark over the 8 days.

28

EXCLUDING OXYGEN AND OXIDANTS

MATERIA

O2 and hydroperoxides can irreversibly react with ruthenium alkylidene catalysts and catalytic intermediates

Dealing with O2

– Degas solution prior to the addition of catalyst

Dealing with hydroperoxides

– Test for peroxides in substrate and solvent

– Store substrate and solvent over BHT

– Purification techniques vary by substrate

29

ETHYLENE IS NOT INNOCENT

MATERIAHong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 7961.

Ethylene can sequester catalyst and lead to decomposition

Remove it during the reaction

− Vacuum / nitrogen sparge / both

− Use a more polar solvent

Vessel size and configuration matters!!!

− Gas transfer effects

− Volume to surface area ratio affects pressure & solubility

30

INTERNAL OLEFINS ENHANCE CATALYST LIFETIME

MATERIAVignon et al ChemSusChem 2015, 8, 1143.

Entry Catalyst Substrate Conv. TON

1 C949 Acrylate 30% 6,000

2 C627 (HG-II) Acrylate 52% 13,800

3 C949 Crotonate 97% 31,100

4 C627 (HG-II) Crotonate 96% 35,450

31

INTERNAL OLEFINS IN TOTAL SYNTHESIS

MATERIAWang, G.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 8088.

Type I

Type II

C627

C848

32

RESIDUAL RUTHENIUM REMOVAL

MATERIA

Ru is Class 2B, same ICH limits as Pd (<10 ppm)

ICH Harmonized Guideline, December 2014

33

RESIDUAL RUTHENIUM REMOVAL

MATERIA

Extraction

• Imidazole - Brenner et al (Boehringer-Ingelheim, Germany) US7183374 (B2), 2007

Mercaptonicotinic acid - Yee, N. K., et al J. Org. Chem. 2006, 71, 7133.

Cysteine - Wang, H. et al Tetrahedron 2009, 65, 6291.

THMP - Pederson et al Adv. Synth. Catal. 2002, 344, 728.

sCO2 - Gallou, F. et al Org. Process Res. Dev. 2006, 10, 937.

Na2S2O5 - Wu, G. G et al WO2010028232, 2010.

Adsorption

H2, Pd/C - Wang et al Org. Process Res. Dev. 2008, 12, 226.

H2, Pd/C - Kong, J. et al J. Org. Chem. 2012 , 77, 3820.

Wheeler, P.; Phillips, J. H.; Pederson, R. L. Org. Proc. Res. Dev. 2016, 20, 1182.

34

FACILITATED BY MINIMAL CATALYST LOADING

MATERIAKong, J.; Chen, C-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey,

J.; Li, H.; Zacuto, M. J. J. Org. Chem. 2012, 77, 3820.

Conditions: (i) Hoveyda-Grubbs II (0.2 mol%), 2,6-dichloroquinone (10 mol%), PhMe (13.5 vol), 100 °C (91%);

(ii) H2, Pd/C, PhMe/IPA, then crystallization from IPA/H2O (89%).

Macrocyclizations on Scale

36

BILN-2061 MACROCYCLIZATION

MATERIA

1. Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang,

X.-j.; Wei, W.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, J.; Tan, J.; Zhang, L.; Xu,

J.; Smith-Kennan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M. Johnson, M. J. Org. Chem. 2006, 71, 7133.

2. Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005,

9, 513.

Context R = C601 Loading (mol %) Concentration Solvent Temp Yield

Initial Scale-Up PNB 5 0.01 M CH2Cl2 40 °C 87%

Pilot Plant (>100kg) Brosyl 3 0.014 M PhMe 80 °C 87%

Early Development Conditions

C601

Hoveyda-Grubbs I

37

FURTHER OPTIMIZATION

MATERIAShu, C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina,

V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303.

R = A:B

H 96:4

Bn 85:15

Boc 0:100

Ac 0:100

Initiation Site Matters

Proposed Chelation

38

FURTHER OPTIMIZATION

MATERIAShu, C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina,

V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303.

Ring strain in product calculated to be ~2 kcal/mol lower when R= Boc versus H.

Conformational Effects

39

FULLY OPTIMIZED CONDITIONS

MATERIAFarina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. Org. Process Res. Dev. 2009, 13, 250.

Key Parameters

2nd Generation Catalyst

− Higher activity

− Thermodynamic control of macrocycle vs oligomers

N-Boc protecting group

− Favors cyclization by reducing ring strain

− Prevents initiation at vinylcyclopropane (epimerization and chelation)

Diene solution degassed by refluxing prior to catalyst addition

40

APPLIED TO SIMEPREVIR

MATERIA

Horvath, A. et al (Janssen Pharmaceuticals, Inc., USA). Improved process for

preparing an intermediate of the macrocyclic protease inhibitor TMC 435. PCT

Int. Appl. 2013061285, May 2, 2013.

Entry R = Time (h) Catalyst loading (mol %) SM (% by HPLC) Oligomer (% by HPLC) Product (% by HPLC)

1 H 20 3.5 59 28 11

2 COCF3 1 3.5 5 n.d. 69

3 COCF3 1 6.4 2 n.d. 94

4 COCF2Cl 1 6.4 n.d. n.d. 95

41

VANIPREVIR OPTIMIZATION

MATERIAKong, J.; Chen, C-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey,

J.; Li, H.; Zacuto, M. J. J. Org. Chem. 2012, 77, 3820.

Catalyst Loading Temp (°C) Additive Addition Method Conc (M) Yield of A (%) Yield of B (%) Oligomerization (%)

0.5 mol % 70 0 mol % Normal 0.09 62 8 5

0.5 mol % 70 10 mol% Normal 0.09 72 <1 5

0.2 mol % 70 10 mol% Normal 0.09 72 <1 5

0.2 mol% 100 10 mol% Normal 0.09 84 1.5 5

0.2 mol% 100 10 mol% With N2 Sparge 0.09 88 1.5 5

0.2 mol% 100 10 mol% With N2 Sparge 0.13 78 2 >15

0.2 mol% 100 10 mol% “Infinite Dilution” 0.13 91 2 5

Capabilities, Services, and Support

43

CATALYST MANUFACTURING AND AVAILABILITY

MATERIA

• Catalyst manufacturing facility in Pasadena, CA

• Metric ton annual capacity

• Kilogram quantities of popular catalysts typically in-stock

• Secondary US manufacturer qualified

• Currently qualifying additional non-US toll manufacturers

44

TECHNICAL SUPPORT

MATERIA

Print and Web Resources

45

CATALYST SCREENING

MATERIA

46

MATERIA

• >40 metathesis catalysts in-house

• Specialized R&D team to help evaluate

• Catalyst selection

• Process optimization

• Application development

• Metric ton catalyst production capacity

• Freedom to operate supported by broadest IP portfolio

• Access to the latest catalyst innovations developed in Professor Grubbs’ labs

• Easy procurement either through

• Sigma-Aldrich for research quantities or

• Directly from Materia for process scale-up and production requirements

MATERIA’S INTERNAL RESOURCES

Philip Wheeler, Ph. D.

Business Development Manager

(626) 584-8400 x298

pwheeler@materia-inc.com

www.materia-inc.com

www.allthingsmetathesis.com

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