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Transforming your chemistr y
Case Studies -Innovative Solutions for Process Oriented
Chemistry
About UsApeiron is a chemical company commercializing olefin metathesis, a Nobel prize-winning technology, to reduce costs and energy inputs while streamlining manufacturing processes in the pharma and chemical industries.
First and foremost, Apeiron strives to offer the best ruthenium catalysts for each unique type of olefin metathesis reaction. Our catalysts have proven to be more efficient than all other commercially available catalysts in a number of applications. The supreme performace is reflected in the supporting data available from a growing number of completed projects conducted for industry-leading customers. Apeiron offers the widest selection of commercially tested ruthenium catalysts on the market, currently available in gram to multi-kilogram quantities.
Second, Apeiron supports its customers in the implementation phase to make the desired processes economi-cally feasible. Olefin metathesis is a relatively new and advanced technology and even skilled chemists struggle to unleash its maximum potential. Apeiron’s experts, specialized in the technology, have become a valuable asset for some of the top R&D teams in the pharma and chemical industries. In this capacity, Apeiron team assists the part-ners as they integrate metathesis into their R&D and production processes.
Apeiron utilizes proprietary, patent protected technology which is the result of an extensive in-house research program as well as external intellectual property licensing from leading industrial and academic partners.
Apeiron Synthesis / © 2018
Case Study 1 - Challenge:
Apeiron’s Solution:
Cathepsin K inhibitorsBoehringer Ingelheim Int.
Increased size of the NHC ligand results in higher functional group tolerance and greater stability of the catalyst.
Catalysts Concentration [M] Catalyst loading [ppm] Isolated yield [%]
Boehringer1 nitro-Grela 0.03 2000 91Apeiron2 nitro-Grela-SIPr 0.2 40 94
The efficiency of olefin metathesis catalysts is often compromised by certain functional groups that may be present in the substrate, solvent or in trace reaction impurities. For example, Lewis bases can coordinate to the metal center of the active catalytic species, trig-gering its decomposition, or form a chelating ligand, reducing catalyst turn-over number. A common means to overcome such interfer-ence is to increase catalyst loading. However, while this seemingly obvious strategy might work for a one-off, small scale reaction, it is an unsustainably expensive solution for larger scale and decidedly not compatible with commercial processes.
Choose the right catalyst and reaction conditions for the job - reduce catalyst loading and boost reaction yield and cost efficiency. Bulkier ligands shield the ruthenium metal center from unproductive coordination, effectively stabilizing the catalyst in the presence of otherwise troublesome functional groups. In the conversion of A to B illustrated below, nitro-Grela (AS2032), our workhorse catalyst for uncomplicated Ring Closing Metathesis (CRM) conversions, was replaced with nitro-Grela-SiPr (AS2033). This simple change affords the desired product in comparable yield, but with 50 times lower catalyst loading and more than 6 times higher concentration.
[1] Boehringer Ingelheim Int. WO 2008/009671 A1[2] Specialty chemicals magazine: issuu.com/fastenerfixingmagazines
RuO
Cl
Cy3P
NN
RuCl
ClN
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O
O
LatMetHeatMet
RuO
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RuCl
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O
LatMetHeatMet
Apeiron Synthesis / © 2018
A ethylene continuously removed B no ethylene removal
Catalyst GC conversion [%]nitro-Grela 72nitro-Grela-SIMes-I24 94
Catalyst GC conversion [%]nitro-Grela 32nitro-Grela-SIMes-I2 65
Case Study 2 - Challenge:
Apeiron’s Solution:
Ring closing metathesis reactions of terminal olefins evolve ethylene as products are formed. The evolved ethylene is a normal me-tathesis by-product and it generally needs to be eliminated from the reaction mixture to enable optimum efficiency and product yield. If not eliminated, ethylene may take part in unproductive metathesis by entering the catalytic cycle in place of the substrate olefin. This competition can dramatically impact the catalyst’s maximum turn-over-number and induce faster decomposition of catalyst. Large scale, batch olefin metathesis processes often suffer reduced process efficiency due to inefficient removal of ethylene from the reac-tor – a potentially serious problem that can force a work-around effort in commercial applications.
The hallmark of Apeiron’s nitro-Grela catalyst family is a very fast initiation. Replacing the chloride anionic ligands with much bulkier iodide anions (nitro-Grela-SIMesI2, AS2053) results in a ruthenium methylidene species having significantly increased selectivity and stability. With typical metathesis catalysts, insertion of larger anionic ligands has little effect on catalyst activity, or may even reduce its activity3. In contrast, nitro-Grela complexes containing iodides stand out as efficient catalysts that are more stable than the parent catalyst and relatively tolerant to the presence of ethylene (and other impurities/by-products) during metathesis of terminal dienes.
Exchange of chlorides to iodides results in more stable ruthenium methylidene speciesand increased catalyst selectivity
[3] a) M. S. Sanford, J. A. Love & R. H. Grubbs, J. Am. Chem. Soc. 2001, 123, 6543–6554 b) J. Wappel, C. A. Urbina-Blanco, M. Abbas, J. H. Albering, R. Saf, S. P. Nolan & C. Slugovc, Beilstein J. Org. Chem. 2010, 6, 1091–1098[4] A. Tracz, M. Matczak, K. Urbaniak & K. Skowerski, Beilstein J. Org. Chem. 2015, 11, 1823-1832
RuO
Cl
Cy3P
NN
RuCl
ClN
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O
O
LatMetHeatMet
O
O
O
8 3
O
Catalyst 200 ppm
Toluene, 70 oCC = 5 mM
Apeiron Synthesis / © 2018
Case Study 3 - Challenge:
Apeiron’s Solution:
Recent advances in ethenolysis of renewable plant oils have created promising new pathways to commercially important specialty chemicals like methyl 9-decenoate and other unsaturated hydrocarbons. Further processing of such compounds with olefin metath-esis leads to precious materials for the polymer industry: e.g., as illustrated below, self-metathesis of methyl 9-decenoate furnishes dimethyl 9-octadecenedioate. The price of production, largely driven by cost of the ruthenium metathesis catalyst needed for efficient conversion, remains a critical factor limiting application of these catalysts in production of bulk chemicals.
Apeiron chemists have developed a catalyst characterized by exceptional efficiency in self-metathesis reactions. The unique design of the catalyst structure results in both high productivity and selectivity. UltraCat ensures high turn-over numbers at extremely low catalyst loadings, a critical performance characteristics for economically feasible dimerization of commodity chemicals
[5] Elevance Renewable Sciences INC US 2013/0204022A1[6] www.materia-inc.com[7] Apeiron Synthesis PCT/IB2016/054486[8] Nalco Sciences US9150468
UltraCat cost per 1 kg of product 0.85 EUR
Catalysts Concentration [M] Catalyst loading [ppm] Conversion [%] TON *
Elevance5 C-8276 neat 17.8 (80 ppm wt) 19 5337Apeiron UltraCat7 neat 2 (11 ppm wt) 71 177250
* Catalyst Turn-over number calculated for productive dimethyl 9-octadecenedioate formation.
Catalyst
neat
CO2Me7MeO2C
7CO2Me
7methyl 9-decenoate dimethyl 9-octadecenedioate
UltraCat cost per 1 kg of product 0.65 EUR
Catalysts AdditiveConcentration
[M]Catalyst loading
[ppm]Yield [%] TON *
Reaction time
Nalco Sciences8
G-II(C-848)6
2-chloro-1,4- benzoquinone neat 2.4 – added in
6 portions 60 125595 6h
Apeiron UltraCat7 – neat 1 – added in 1 portion 63 315850 1h
* Catalyst Turn-over number calculated for productive dimer formation
n n n
Catalyst
neat, 60 oC
Apeiron Synthesis / © 2018
Case Study 4 - Challenge:
Apeiron’s Solution:
Polydicyclopentadiene, poly(DCPD), a polyolefinic, cross-linked, thermoset material exhibits outstanding thermal stability, mechani-cal strength, fracture toughness, and dielectric characteristics. Thanks to these properties poly(DCPD) has become a very attractive polymer for numerous applications and remains one of the most ubiquitous Ring Opening Metathesis Polymerization (ROMP) materials in industrial uses.
The most effective catalysts for DCPD polymerization should exhibit optimal ROMP kinetics and should allow facile handling of the monomer/catalyst formulation. Limitations of currently used ruthenium catalyst relate to the difficult initiation control and poor solubility in neat monomer (requires solvents for solubilization). Both aspects can compromise the physical properties of the resulting polymer9.
Apeiron chemists have developed a versatile set of ROMP catalysts, soluble in DCPD monomer, that provide precise control of ROMP initiation with thermal or chemical triggers. 20 ppm of HeatMet (AS2055) initiates the reaction at temperatures above 60°C to afford quantitative yields of poly(DCPD). LatMet (AS2035) is a latent catalyst that remains dormant in DCPD until its activation with hydrochlo-ric acid, whereupon it affords full conversion within just 10 minutes. Mechanical properties of the resulting materials are in accordance with those representative for industrially produced and applied poly(DCPD).10
Polymer Characteristics HeatMet LatMeta pDCPDb Telene® Metton®
Rm maximum strain [MPa] 46 29 37-41 43 46.8E Young’s modulus [GPa] 1.66 1.75 1.65-1.93 1.87 1.96
[9] A. Kozłowska, M. Dranka, J. Zachara , E. Pump, C. Slugovc, K. Skowerski & K. Grela, Chemistry 2014, 20, 14120-14125[10] a) Polymer material property database EFUNDA10 b) C. Slugovc, “Industrial Applications of Olefin Metathesis Polymerization” in Olefin Metathesis: Theory and Practice, 1st ed. (Ed.: K. Grela), Wiley, Hoboken, Weinheim, 2014, p. 329– 333.
a) Chem. Eur. J. 2014, 20, 1.b) Polymer material property database EFUNDA
RuO
Cl
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RuCl
ClN
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O
O
LatMetHeatMet
RuO
Cl
Cy3P
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RuCl
ClN
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O
LatMetHeatMet
Apeiron Synthesis / © 2018
Case Study 5 - Challenge:
Apeiron’s Solution:
In many R&D and commercial applications, heavy metal contamination of reaction products is an important concern. Residual ru-thenium and ruthenium complexes may catalyze side reactions or adversely impact yields of the subsequent synthetic steps.11 Final product contamination may also be of critical importance. For example, in the pharmaceutical industry, regulations require that the maximum ruthenium contamination in active pharmaceutical ingredients be limited to no more than 10 ppm. It is common to observe ruthenium contamination greater than 2500 ppm following an olefin metathesis reaction.
Apeiron chemists designed and developed a new heterogeneous catalyst.12 FixCat/SBA-15 (AS2062) is a ruthenium metathesis cata-lyst, supported on SBA-15, that delivers high turn-over number with minute traces of leaching. FixCat/SBA-15 is fully compatible with both flow chemistry and batch processes, allowing catalyst reuse (> 20 runs) and routinely affords ruthenium product contamination below 5 ppm. The effectiveness of FixCat/SBA-15 in catalysis of a RCM reaction, in both batch and continuous flow modes, is shown in the figures below.
[11] H. Wang, H. Matsuhashi, B. D. Doan, S. N. Goodman, X. Ouyang, W. M. Clark Jr., Tetrahedron, 2009, 65, 291-6303[12] K. Skowerski, J. Pastva, S. J. Czarnocki, J. Janoscova, Org. Process Res. Dev., 2015, 19, 872-877
Batch reaction – 1 h batch runs resulted in cumulative TON of 35,000 for catalyst FixCat/SBA-15 (blue bars) com-pared to AquaMet (AS2038) (purple bars)
Continuous flow setup – efficiency comparison for different FixCat loadings on SBA-15. Non-covalent catalyst immobilization allows facile modulation of the catalyst loading to maximize TON
or to maintain high conversion levels.
FixCat/SBA-15; 5 wt%FixCat/SBA-15; 0.25 wt%
Time [h]
Con
vers
ion
[%]
00
102030405060708090
100
10 20 30 40 50
Run
Con
vers
ion
[%]
100
90
8070
60
50
4030
20100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
RuO
Cl
Cy3P
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RuCl
ClN
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LatMetHeatMetRu
O
Cl
Cy3P
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RuCl
ClN
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LatMetHeatMet
Apeiron Synthesis / © 2018
Concentration [M] Catalyst loading [ppm]
Requested 0.5 2000
Apeiron’s result 1.5 300
A large specialty chemicals manufacturer wanted to reduce production costs for a macrocyclic product using a new, more efficient process that incorporated a RCM step. Internal efforts led to a process that worked but with high solvent use, due to the high dilution conditions required, and with unacceptably high catalyst loading – catalyst cost for a production run was projected to be higher than the market price for the final product.
Effective Molarity [mM] Catalyst loading [ppm] Catalyst price
Customer’s result 5 25000 5 x product price
Apeiron’s result 20 50 acceptable
Case Study 6Apeiron Partner Challenge:
Apeiron’s Solution:
Following four months of optimization effort, Apeiron chemists provided the partner an efficient process with 6 times lower catalyst loadings than specified (500 times lower than the original process). Additionally, reaction concentration and yields were increased four- and twofold respectively.
Alternative pathways towards a troublesome small heterocyclic molecule were investigated by a partner company. One of the most attractive synthetic route designs entailed a three-step process, with RCM, as the key step, in closing the fused 6-membered hetero-cyclic ring. Unfortunately, an extended effort in process development failed to afford the target molecule in appreciable yields using the olefin metathesis-based pathway. An economically viable RCM process was required to continue with this route.
Case Study 7Apeiron Partner Challenge:
Apeiron’s Solution:
A one week proof-of-concept study at Apeiron confirmed the process viability using a closely related, readily available substrate. This success triggered a two month optimization effort whereupon Apeiron successfully obtained the required product with dramatically im-proved process parameters. The partner required a maximum catalyst load of 2 000 ppm and substrate concentration of at least 0.5M in the final process. Apeiron delivered a process with substrate concentration of 1.5M and 300 ppm catalyst loading, using Apeiron’s nitro-Grela (AS2032) flagship catalyst, resulting in process costs for catalyst alone > 6 times lower than the partner’s requirements.
Apeiron Synthesis / © 2018
North AmericaApeiron Synthesis, Inc Cambridge Innovation Center, 1 Broadway , Cambridge, MA 02142 USA
Grazyna Szymanska, PhDGlobal Business [email protected]: (+1) 781-608-5859
EuropeApeiron Synthesis S.A. Wroclaw Technology Parkul. Duńska 9, 54-427 WrocławPoland
Joanna DrygajłoSales Manager and Technical Support [email protected].: (+48) 71-798-5621
Catalyst loading [wt ppm]
Requested 40Apeiron’s result 8
A commodity chemicals manufacturer was seeking a feasible process to obtain a new polymeric material with specific properties. Two key parameters to meet were: i) low polydispersity and ii) extremely low catalyst loading, due to narrow profit margins in commodity polymers.
Case Study 8Apeiron Partner Challenge:
Apeiron’s Solution:
Despite the high expectations, Apeiron successfully applied olefin metathesis in the bulk chemistry process. In just one month, our team managed to meet both process and product parameters requested by the customer. With the catalyst loading as low as 8 wt ppm, costs of the metathesis step were reduced fivefold relative to the threshold set for economic reasons. Importantly, the optimiza-tion was conducted on unprocessed materials provided by the customer. Final catalyst cost reached 0.45 EUR per kg of the product.
Apeiron Synthesis / © 2018
