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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
8
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.
10
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.
11
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
13
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
14
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
15
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%
16
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
17
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
18
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
19
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
20
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
22
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)
23
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.
24
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
25
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%
26
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
www.materia-inc.com
www.allthingsmetathesis.com
© 2016 Materia, Inc.
60 N San Gabriel Blvd.
Pasadena, CA 91107