The impact of high-throughput catalyst screening in drug discovery

The recent trend of chemical catalysis centers and industry-academia partnerships has led to an influx of new reactions with direct applications for medicinal chemists1.  High-throughput experimentation (HTE) approaches have significantly lowered sample and time requirements necessary to screen thousands of unique reaction combinations for the discovery of new catalysts and reactions.  Recent advances in photochemistry2, late-stage functionalization3 and generating scaffold diversity4 are intriguing new possibilities to access structural complexity, while classical favorites like Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions have seen continued advances in catalyst design and reaction protocols5. Certainly, many medicinal chemists would like to incorporate new technology and chemistry into their programs; however, testing and implementing new techniques on early discovery timelines and budgets can be difficult.  With many options available to plan and execute the synthesis of a new series, the medicinal chemist remains tasked with producing testable amounts of unique material on short timelines.   How best can the medicinal chemist leverage new technology and chemistry to bring value to their program? How can small and mid-sized medicinal chemistry programs compete without millions in upfront investment to establish their own catalysis centers? To start to answer these questions, it is best to start at the beginning of the typical early discovery project. 

Implement New Chemical Technology

 

Modern chemistry has afforded screening libraries containing millions (billions!) of compounds which are tested for activity using high-throughput screening (HTS) techniques.    From this list of hits, the medicinal chemist has many options when setting a path forward for synthesis of a new series where diverse compounds are needed to fill out chemical space.  Molecular modeling and cheminformatics tools give the designer varied approaches to propose structures with a virtually unlimited array of predicted properties6.  It is a certainty that the designer can plan a list of targets faster than they can be synthesized. On paper (or a computer screen) all structures seem accessible and together serve to answer the biological hypothesis proposed.

A common total synthesis trope rephrased in many ways, “with enough time, energy and money any structure can be synthesized”. The field of natural product total synthesis has validated this assertion as some natural products, like observed for the successful synthesis of Maoecrystal V, required upwards of a thousand screening steps to find a suitable reaction for just one step of the scheme7.  With unlimited time, budget and robotics (or graduate students), one could test nearly every possible combination of known catalysts and reagents to find a working synthesis for every structure in development. This is, however, of no comfort to those at the forefront of early discovery where timelines and budgets are short with access to equipment often limited.

Each failed reaction is a missed opportunity

 

In early discovery, synthetic strategies which aspire to build structural complexity in as few reactions steps as possible are preferred.  Many strategies will invoke designing fragments of the molecule with connecting the structure in a late step with a cross-coupling reaction like a Suzuki or a Buchwald-Hartwig amination. Achieving the diversity proposed in the series design, will likely require many reactions with a diverse array of coupling partners, wildly varied reactivity and potentially incompatible functional groups, testing the effectiveness of these common coupling reactions.  As a first pass, a single catalyst and protocol may be selected to screen a diverse set of functionalized building blocks. Many of these reactions will undoubtedly work the first time and no additional reaction optimization will be necessary.  In early discovery, only a few mg of compound may be necessary for initial screening/testing and this may be accessible with minimal optimization.  However, an internal analysis of electronic notebook data for synthetic plans at Merck found that 55% of metal catalyzed C-N forming reactions in what were to be final steps of synthesis found no product at all8.  How to resolve this disconnect between the utility of the common cross-coupling reactions and the preponderance of failed reactions in real world scenarios? What implications do the missed reactions have on the success or failure of a project?

figure_1

Each failed reaction is a missed opportunity in a carefully planned series design. In a chemical space analysis performed by a research group at Merck, the majority of drug compounds based on cross-coupling chemistry fell far outside the chemical space covered by substrates in the initial methodology literature8. The structures most likely to be valuable from a medicinal chemistry perspective fall well outside the scope of successful reactions in the literature as presented and will likely require reaction optimization.  If too narrow a spectrum of catalysts is attempted or too little effort to resolve a problem reaction, you may miss a product which could be your next drug.  Extensive efforts are needed to improve the success rates for synthetic methodology on biologically relevant molecules to be useful in medical chemistry.

From Literature To The Chemist Bench

 

Literature methods are often reported using simple substrates demonstrating the high yield and utility of a new catalyst or reaction protocol. Comparing literature reports which rarely use the same substrate, scale, solvent or protocol makes direct comparison very difficult.  HTE tools enable analysis of reaction robustness for real world substrates on a standardized scale in broad depth in ways that are extremely difficult without automated tools.    A Merck group published a detailed analysis of cross-coupling chemistry using what they have termed Chemistry Informer Libraries8.  Using a pre-selected array of 24 boronate substrates, the group tested first generation palladium catalysts for the Suzuki coupling of a “simple” (aryl) bromide.  For 24 substrates, using the original Suzuki protocol and catalyst, Pd(Ph3P)4, 22 of 24 reactions gave higher than 20% with an average yield of 46%.  Switching to an aryl chloride with the same set of boronates, more variation was observed.  For the chloride, using Xphos G2 pre-catalyst, 20 of 24 reactions were greater than 20% for an average of 57% including 4 examples with greater than 98%. Interestingly, for the more evolved Xphos catalyst, 3 of the reactions report 0 % conversion. By changing temperature and other reaction parameters they show even more variation and selectivity.  It is easy to imagine the complexity that could be expected when expanding this analysis to additional Suzuki catalysts and more complex coupling partners.  However, by using a standard set of substrates this method of analysis allows direct comparison of reaction protocols.

 

figure_2

In the same report but for C-N bond formation, 8 catalyst and base combinations were screened with an informer library of 18 halides with a secondary amine.  The first condition reported by Buchwald and Hartwig using ((P(o-Tol)3)2PdCl2 was successful in only 2 of the 18 reactions at greater than 20%.  The most successful catalyst RuPhos G2 precat with Cs2CO3 gave only 6 reactions greater 20%.  For the 8 conditions tested, successful reactions ranged from 2-6 trials, although interestingly yields for individual reactions were as high as 99% demonstrating the varied reactivity that can be observed by reaction screening.  However, this work confirmed the difficulties observed for the C-N formation.

1536 Reaction Conditions in Parallel

 

When the reaction can be miniaturized and automated, the number of reactions possible is staggering.  Recently, the Merck Process Group reported their platform for high throughput experimentation for synthetic route scouting9.  Transitioning from microvials to 1536 well microtiter plates for 1 ul scale reactions, the nanomolar techniques represent the state of the art in the lower limits for testing chemical reactivity and reaction handling. For this work, they looked to the miniaturization of palladium cross-coupling reactions, including C-N bond formation, which as discussed above show difficulty on real-world substrates.  Focusing on finding a reaction that worked in DMSO and at room temperature, the group screened 16 second and third generation palladium pre-catalysts with 6 superbases for 96 unique reaction conditions. For a single bromide substrate with 16 nucleophiles and the 96 reaction conditions in one 1536 microtiter plate, using nanoliter dosing and rapid MISER HPLC-MS batch analysis the group was able to screen 1536 reactions in one day. This setup required only 0.02 mg material per reaction. Extension to additional substrates and reaction option led to a series of new nanoscale hits, with the validation reactions repeated at 1000x scale (~25 mg).  This HTE approach led to a new reaction protocol (or more accurately, a reaction screen) applicable to biologically relevant structures, where 21 complex products were synthesized at scale previously synthetically inaccessible. This work pushes the extent to which synthesis should not limit access to a molecule for probing a biological hypothesis.

As HTE tools further probe the synthetic toolkit, how best to merge the potential wealth of knowledge available from these systems for applications available to the bench chemist?  Most chemists do not have access to the type of instrumentation driving HTE experiments, certainly not at the discovery stage. Even with access, the instrumentation may not be supported by discovery budgets.  Screening thousands of conditions for one compound, in one program is not likely to be cost effective. When the chemistry is amenable to automation, as discussed, tools exist to screen thousands of reactions.  However, the setup, use and availability of a tool to screen 1536 may not be appropriate to screen conditions for just one product.  While easy to setup to run 1536 reactions, may not be the right tool to test 16 or 32 reactions for a single optimization.

When selecting the best approach to resolve reactions that do not work in a first pass, the medicinal chemist is forced to ask the question, “How much time and effort should I put into trying to make this structure?”  Once it is determined that optimization or screening is necessary, what options exist? With unlimited time, budget and robotics, one could test every possible combination to find the optimal reaction to make a new structure, and even develop some new chemistry along the way. However, at the bench, practical limitations exist. While designing an optimization, the easiest solution may be to select a few additional catalysts off the shelf (based on what is readily available), or try an extra base or a different solvent. A common limitation is the question “How many things do I want to weigh today?  For air and water sensitive reactions, this is an added burden and a further detriment to undertaking a large screen.

figure_3

Tools for reaction optimization are certainly not new and include everything from low to high tech solutions.  Parallel sets of reaction vials set up one at a time in the hood, specialized reaction blocks like the optiblock™ or bench top liquid handling units all afford the medicinal chemist to opportunities to screen catalytic reactions. However, the missing feature in many cases is the chemistry to use in the setup. Automated tools may sit unused while the hood is full of flasks and vials due to a lack of chemistry to fill an extensive array or the time required to setup the apparatus.

Finding the appropriate chemistry for a screen can be difficult. For example googling “Suzuki coupling catalysts” or turning to Scifinder™ to determine the best condition to fit each attempted coupling will reveal more than 50 commercially available palladium catalysts and thousands of literature references to decipher.    Several generations of palladium pre-catalysts have been development to accommodate a wide range of ligands to improve stability, reactivity, turnover and functional group tolerance10. How long does it take to select, order and test the new catalyst? Is 1 g of a new palladium catalyst necessary when only a few mg are necessary to test an unknown reaction?  Newly available catalysts and protocols are limited by the barrier between the literature and medicinal chemistry applications and require vetting.  Here the lessons learned from HTE studies can be informative.

HTE techniques to vet catalysts and reaction protocols for real world compounds in early discovery can inform medicinal chemistry programs even without access to the most technologically advanced chemical screening techniques. Data from HTE experiments like the Merck chemical informer libraries and other methodology studies represent opportunity to establish pre-designed arrays of chemical catalysts to be part of the standard medicinal chemist’s workflow. Standardizing knowledge learned from the many HTE experiments can be an opportunity to delivery chemistry to the medicinal chemist in easy to use formats increasing compound output and complexity without the need for access to HTE technology.

Pre-designed arrays of chemical reactions

 

Pre-designed catalyst kits represent a significant opportunity to both enhance discovery efforts by increasing the complexity of targets while saving time and money in the process.  Pre-weighed reagents and catalysts packed under inert atmosphere facilitate screening of reaction conditions quickly without the need to use a glove-box to manipulate air sensitive or moisture sensitive reagents.  Kits are prevalent in nearly all biochemical and molecular biology labs from the smallest academic to the largest of pharma. The use of kits in chemistry; however, remains rare even though reaction optimization is highly amenable to standardization.  Catalyst and reagent screening kits with pre-designed reaction conditions for the bench chemist can fill the gap between haphazardly screening a few catalysts or reagents that can be readily found near one’s own benchtop and extensive and time consuming literature searches for screen design.

For chemistry applications, “kits” has often taken on an unfortunate description.  Catalyst “kits” available from many suppliers may only contain 100 mg or more of each of a wide array of catalysts.  While convenient for ordering purposes, still require significant setup of the reaction and are often a limiting factor towards the utility of the full set of catalysts. To be truly beneficial, a kit should include all of the necessary components to run the reaction including reaction vessel.  Fully designed individual reactions overcome this burden of weighing and handling air and water sensitive reagents.  Catalyst screening kits for Suzuki-Miyaura, Buchwald-Hartwig amination and several other reactions are now commercially available11,12. These kit formats should be amenable to a broad range of chemistry.  New validated chemistry can be delivered to the bench chemist in easy to use formats quickly accommodating the adoption of new methodology without the burden of researching, designing and validating unknown chemistry.

 

Summary

 

Designing a reaction screen can be time consuming, inefficient and ultimately unsuccessful.   Weighting small quantities of catalysts under inert conditions is a large barrier to screening a wide array of conditions. As a result, the attempted screen will likely be compromised or hindered in some way, either in scope, scale or ultimately be given up entirely for higher priority or easier targets. Often after a few hurdles or setbacks, the structure that looked so important in the planning stages is discarded for expediency. However, each structured missed is an opportunity lost. Fewer and lower quality compounds synthesized results in less informed decisions when testing biological hypotheses. Screening kits with pre-designed reaction conditions for the bench chemist can fill the gap between haphazardly screening a few catalysts or reagents readily found near one’s own benchtop and extensive time consuming literature searches for screen design. Pre-designed catalyst kits represent a significant opportunity to both enhance discovery efforts by increasing the complexity of structure while saving time and money in the process.

Who we are:

HepatoChem: (a chemical technology company located in Beverly, MA for metabolite production, lead diversification of analogues and chemical kits for reaction screening.  HepatoChem specializes in developing catalyst platforms for late-stage functionalization and cross-coupling reactions with a focus on designing reaction arrays for specific functions. Two highlights include a biomimetic oxidation platform for metabolite production and late-stage fluorination.

What we offer:

EvoluChem Reagent/Catalyst kit systems enable handling arrays of air and water sensitive reagents without the need for a glove box or robotics. Kits solve a need for the bench chemist allowing quick screening of catalysts and reaction conditions to identify the fastest route for selecting a reaction of interest.  In addition to chemical kits for cross-coupling catalysis, HepatoChem offers kits for amide coupling, late-stage functionalization and biomimetic oxidation for metabolite production.

For further information, please contact info@hepatochem.com.

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References:

(1) Quentin Michaudel, Yoshihiro Ishihara, and Phil S. Baran, “Academia–Industry Symbiosis in Organic Chemistry” Accounts of Chemical Research 2015, 48 (3), 712-721.

(2)  Megan H. Shaw, Jack Twilton, and David W. C. MacMillan, “Photoredox Catalysis in Organic Chemistry” J. Org. Chem. 2016, 81, 6898-6926

(3)  Tim Cernak, Kevin D. Dykstra, Sriram Tyagarajan, Petr Vachal, and Shane W. Krska, “The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules” Chem. Soc. Rev. 2016, 45, 546-576.

(4) M. Garcia-Castro, S. Zimmermann, M. G. Sankar, K. Kumar, Angew. Chem. Int. Ed. 2016, 55, 7586.

(5)  (a.)  Miyaura, N.; Yanagi, T.; Suzuki, A. The palladium-catalyzed cross-coupling reaction of phenylboronic acid with haloarenes in the presence of bases. Synth. Commun. 1981, 11, 513−519. (b.) Paul, F.; Patt, J.; Hartwig, J. F. Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in the hetero cross-coupling of aryl halides and tin amides. J. Am. Chem. Soc. 1994, 116, 5969−5970.  (c) Guram, A. S.; Buchwald, S. L. Palladium-catalyzed aromatic aminations with in situ generated aminostannanes. J. Am. Chem. Soc. 1994, 116, 7901−7902.

(6)  For a comprehensive list of available cheminformatics software available, See  http://www.click2drug.org/

(7)  Artiom Cernijenko, Rune Risgaard, and Phil S. Baran, “11-Step Total Synthesis of (-)-Maoecrystal V” J. Am. Chem. Soc., 2016, 138, 9425-9428.

(8) We direct the reader to this excellent open access article:  Kutchukian, P. S.; Dropinski, J. F.; Dykstra, K. D.; Li, B.; DiRocco, D. A.; Streckfuss, E. C.; Campeau, L.-C.; Cernak, T.; Vachal, P.; Davies, I. W.; Krska, S. W.; Dreher, S. D. Chemistry informer libraries:  a chemoinformatics enabled approach to evaluate and advance synthetic methods.  Chem. Sci. 2016, 7, 2604− 2613.

(9)  Buitrago Santanilla, Alexander; Regalado, Erik L.; Pereira, Tony; Shevlin, Michael; Bateman, Kevin; Campeau, Louis-Charles; Schneeweis, Jonathan; Berritt, Simon; Shi, Zhi-Cai; Nantermet, Philippe; Liu, Yong; Helmy, Roy; Welch, Christopher J.; Vachal, Petr; Davies, Ian W.; Cernak, Tim; Dreher, Spencer D.  Nanomole-scale high-throughput chemistry for the synthesis of complex molecules, Science, 2014, 347, 49-53.

(10) Ruiz-Castillo, Paul and Buchwald, Stephen L. “Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions” Chem. Rev., 2016, 116, 12564-12649.

(11). For a full catalogue of reagent and catalyst screening kits visit www.hepatochem.com.

(12)  KitalysisTM from Aldrich Millipore.

 

 

 

 

How do you handle hygroscopic salts?

Salts such as weak bases are omnipresent in organic chemistry. The conversion rate of a reaction can be greatly affected depending on the salt. While it is easy to weigh K2CO3 or Na2CO3, salts such as Cs2CO3 or K3PO4 are more difficult to handle when the reaction conditions require anhydrous solution.
No need for glove box
 
When you want to test a hydroscopic salt you need to be able to weigh them in moisture free environment which requires the use of a isolation equipment such as a glove bag or a glove box. Because glove box is not common in organic synthesis laboratories; Therefore, chemists often pass on important salts such as potassium phosphate or cesium carbonate.
Using pre-filled reaction vials
Pre-filled reaction vials allow to handle hydroscopic salts without the need for an isolation chamber. By simply injecting your reaction solution through the septum using a syringe you can try multiple salts and optimize your chemistry.
IMAG0627
We manufacture pre-filled in controlled environment and offer several vial formats that could fit any type of reaction setup. You can conveniently screen every relevant salts in one experiment.

 

  • Reaction vials pre-filled with reagents and stir bar.
  • Multiple format and vials available
  • Microwave or conventional heating
  • Pre-designed or custom arrays available
  • Reagents are packaged under inert atmosphere

Learn more about our kits at http://www.hepatochem.com/chemistry-kits/prefilled-reaction-vials/

ACS Expo 2016 August 21st-23rd


ACS Expo 2016 August 21st-23rd
Please come visit HepatoChem Booth #338 at the 252nd American Chemical Society National Meeting & Exhibition to discover our new catalog of chemistry kits.
 
Late stage functionalization kits
  • Reaction vials pre-filled with reagents and stir bar.
  • Multiple format and vials available
  • Microwave or conventional heating
  • Pre-designed or custom arrays available
  • Reagents are packaged under inert atmosphere

Learn more about our kits

Amide Coupling in Medicinal Chemistry

In recent years, amide coupling has become the most frequently used reaction in medicinal chemistry1.  Found as the backbone of proteins, the amide bond is nominal formed by the condensation of a carboxylic acid and an amine.  Due to a nearly unlimited set of readily available carboxylic acid and amine derivatives, amide coupling strategies can be an efficient approach for medicinal chemists to generate novel compounds.  As a result of this utility, a nearly unlimited set of reagents and protocols have been development to afford this simple transformation of amide bond formation2,3.

Amide Bond Formation

amide_bond_formation

The most common method for formation of an amide bond is the condensation of a carboxylic acid and an amine.  Generally, the carboxylic acid needs to be activated in order to react with the amine while remaining reactive functional groups need to be protected.  This process occurs in two steps in either one pot with direct reaction of the activated carboxylic acid or in two steps with isolation of an activated “trapped” carboxylic acid with reaction with an amine.

Two step peptide bond formation

two_step_peptide

The carboxylate reacts with the coupling reagent yielding a reactive intermediate which can often be isolated or used immediately with an amine to form an amide bond.  A wide variety of reagents have commonly been used to generate the activated carboxylic acid such as an acid halide (chloride, fluoride), azides, anhydrides, or carbodiimides.  Additionally, active esters such as pentafluorophenyl or hydroxysuccinimido esters can be prepared as reactive intermediates.  Reactive intermediates derived from generation of acyl chlorides or azides are highly efficient for amide coupling; however, their harsh formation and high reactivity often limits use with complex substrates or amino acids.  A broadly applicable method for the formation of amide bonds use carbodiimides such as DCC (dicyclohexylcarbodiimide) or DIC (diisopropylcarbodiimide) for activation.  Additives are often required to improve the efficiency of the reactions especially for solid-phase synthesis.

common_carbodiimides_additives

To avoid side reactions involving the substituents on the two coupling components, it is often necessary to carefully select the appropriate peptide-coupling reaction condition.   One common problem with the use of carbodiimides is the racemization of amino acids.   To remedy this, two classes of coupling reagents:  Phosphonium and aminium reagents represent significant improvements over carbodiimide methods.

Common Aminium reagents

common_aminium_reagents

Common Phosphonium reagents

common_phosphonium_reagents

Aminium salts are very efficient peptide coupling reagents with quick reaction times and minimal racemization.  With the addition of an additive such as HOBt, racemization can be completely eliminated.  Aminium reagents are used in equal molarity to the carboxylic acid to prevent excess reagent reacting with the free amine of the peptide preventing coupling.  Phosphonium salts react with carboxylate requiring usually 2 equivalent of base.  (such as DIEA).  One key advantage for the use of phosphonium salts over iminium reagents is that phosphonium does not reactive with the free amino group of the amine component.  This allows couplings to occur in equimolar relation between the acid and amine, highly advantageous in situations such as the intramolecular cyclization of linear peptides or examples where excess of valuable amine component is discouraged.

Choosing the correct reaction for your needs:

While amide bond formation is a straightforward reaction, the choice of suitable reagents for an individual coupling of a complex carboxylic acid and amine may be a difficult decision.  A variety of factors can be involved in finding the optimal peptide coupling reaction.  Unanticipated side reactions or rearrangements, low conversions, solubility issues, or incompatibility with additional synthetic steps can all hinder what would appear to be a straightforward amide coupling reaction.  As such, it is often necessary to draw from the large number of available reagents and protocols to find the optimal reaction condition.  Screening a selection of reagents can often find a suitable reaction for any amide coupling.

 

References:

 

1.  Brown, Dean G., Bostrom, Jonas, “Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry:  Where Have All the New Reactions Gone?” J. Med. Chem., 2015, ASAP.

2.  El-Faham, Ayman; Albericio, Fernando, “Peptide Coupling Reagents, More than a Letter Soup” Chem. Rev., 2011, 111, 6557.

2.  Pattabiraman, Vijaya R., Bode, Jeffrey W. “Rethinking Amide Bond Synthesis” Nature, 2011, 480, 471.

Magic methyl in medicinal chemistry

Methyl groups are very common in drug molecules. As reported by Heike Schonherr and Tim Cernak1, more than half of the top-selling drugs contains a CH3. A simple substitution of a C-H with a methyl can increase the potency of a compound by more than 100-fold.

The effect of C-H methylation primarily affects the conformation of the original molecule.  Based on this reported statistical analysis2 the effect of methyl can be equally positive or negative. However a positive effect could be decisive in a drug discovery program.

Effect of ortho substitution3,4.

ortho_methylation1

ortho_methylation2

Effect of ring substitution5

ring_methylation

Effect on rotatable bond6

bond_methylation

Even if the methyl can be seen as a potential hot spot for metabolism. The addition of the methyl next to a metabolism position can improve metabolic stability.7

Methyl_stability

 

Contact us at info@hepatochem.com

 

  1. Heike Schonherr and Tim Cernak, Angew. Chem Int. Ed. 2013, 52, 12256-12267
  2. C. S. Leung, S. S. F. Leung, J. Tirado-Rives, W. L. Jorgensen, J. Med. Chem. 2012, 55, 4489 – 4500.
  3. F. Berardi, C. Abate, S. Ferorelli, A. F. de Robertis, M. Leopoldo, N.A. Colabufo, M. Niso, R. Perrone, J. Med. Chem. 2008, 51, 7523 – 7531.
  4. J. Y. Hwang, D. Smithson, F. Zhu, G. Holbrook,M. C. Connelly, M. Kaiser, R. Brun, R. K. Guy, J. Med. Chem. 2013, 56, 2850 – 2860.
  5. P. J. Coleman and coll. , Chem- MedChem 2012, 7, 415 – 424.
  6. G. F. Costello, R. James, J. S. Shaw, A.M. Slater, N. C. J. Stutchbury, J. Med. Chem. 1991, 34, 181 – 189.
  7. R.W. Friesen and coll., Bioorg. Med. Chem. Lett. 1998, 8, 2777 – 2782.

 

 

Buchwald palladium precatalysts

Palladium based catalysis is the most used tool to perform the formation of C-C, C-O and C-N. There are many sources of palladium such as PdOAc2, PdCl2 or Pd2dba3. However the related methods do not always allow sufficient conversion.

Palladium precatalysts is an efficient solution to generate in-situ the LnPd(0) needed for the reaction. These precatalysts are generally air and moisture stable.

The first palladacycle precatalyst has been reported by Herman and Beller in 19951. Since then Buchwald laboratories has developed several types of palladium.

The first generation of Buchwald palladium precatalysts are phenethylamine derivatives. In presence of a base the LPd(0) can be generated in-situ.

1st_generation_precatalysts_activation

 

The second generation of Buchwald palladium precatalysts are 2-aminobiphenyl derivatives. These precatalysts can be activated at room temperature.

2nd_generation_precatalysts_activation

The third generation of Buchwald palladium precatalysts are methylsulfonate salt of 2-aminobiphenyl derivatives. These precatalysts are compatible with bulky ligands and show longer stability in solution.

3rd_generation_precatalysts_activation

The fourth generation of Buchwald palladium precatalysts are methylsulfonate salt of 2-methylaminobiphenyl derivatives. These precatalysts are compatible with bulky ligands and show longer stability in solution.

4th_generation_precatalysts_activation

 

try_precatalyts_kit

 

1 Herman,W.A.; Beller,M. Angew. Chem. Int. Ed., 1995, 34, 1844-1848.

 

Why is fluorine so attractive to medicinal chemists?

In medicinal chemistry, fluorine substitution of alkyl or aryl hydrogen is an increasingly popular strategy to optimize lead compounds. Fluorine offers unique properties. It is almost as small as a hydrogen but very electronegative. The C-F bond is highly polarized.

Conformation effect of fluorine

The polarity of the C-F bond influences the conformation of aliphatic systems.

conformation_fluorine

It is generally accepted that fluorine can interact with hydroxyl, amine and amide functions through hydrogen bond interaction and induce specific conformation.

hydrogen_bond_fluorine

Influence on pKa, permeability and pharmacokinetic properties of fluorine

The electron-withdrawing properties of fluorine can reduce pKa of amines and make them less basic. The similar effect is observed on carboxylic acids and make them more acidic. The change in pKa will influence conformation, potency, permeability, and pharmacokinetic properties.

pKa of fluorinated acids, alcohols or amines

CH3CO2H      4.8       CH2FCO2H    2.6

(CH3)2CHOH 17.1     (CF3)2CHOH  9.3

CH3CH2NH2  10.7      CF3CH2NH2   5.7

Improve metabolic stability

Because of the strength C-F bond, fluorine substitution of a hydrogen is a common way to improve stability. It can be done in both aliphatic and aromatic systems. Fluorine will also increase metabolic stability of electron-rich aromatic ring.

 

Learn how to add fluorine in your lead compounds here.

 

Read more
Eric P. Gillis, Kyle J. Eastman, Matthew D. Hill, David J. Donnelly, and Nicholas A. Meanwell, Applications of Fluorine in Medicinal Chemistry, J. Med. Chem., 2015
http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00258

 

Contact us at info@hepatochem.com

HepatoChem Presenting at the ACS Meeting in Boston, MA

Dr Ryan Buzdygon will be presenting “Late-stage functionalization platform for lead optimization and diversification: Generation of high value compounds directly for biological testing” at ACS Boston. Stop by on Wednesday August 19th during the General Posters Session for the Division of Medicinal Chemistry from 7:00 PM – 9:00 PM in the Ballroom at the Boston Convention & Exhibition Center to hear about our late stage diversification platform.

HepatoChem @ Drug Discovery Chemistry Conference

HepatoChem will be present at the tenth annual Drug Discovery Chemistry on April 21-23, 2015 in San Diego. Please come and see us at the booth 34.

HepatoChem and XenoTech Announce Exclusive Partnership

 

Lenexa, KS, August 19th, 2014 — XenoTech announces an exclusive partnership with HepatoChem to offer fast and cost-effective metabolite production from bioactive small molecules. Based on an innovative and proprietary chemistry platform, the technology enables convenient and timely assessment of critical metabolite and toxicity issues. According to XenoTech’s Vice President of Commercial Operations, Christian Darabant, “the value of rapid metabolite synthesis for assessing clinical risk can be measured directly by comparison with the approximate $2 million per day cost impact of each day of delay in a drug’s development.”
Metabolite synthesis is critical in the drug development process as it allows researchers to accurately evaluate metabolites in safety toxicity as well as promoting identification and isolation of pharmacologically active metabolites. According to Marc Bazin, HepatoChem’s CEO, “current technologies are designed to identify metabolites but are unable to produce testable quantities of metabolites. Consequently, metabolite studies are delayed (a calculated risk) in the drug delivery process; having access to milligram quantities of drug metabolite permits resolution of many of the fundamental questions surrounding small molecule metabolism. The biomimetic technology speeds up metabolite studies to allow rapid improvement of the metabolic properties of drug candidates.” XenoTech’s Executive Vice President & COO, Jason Neat, further explains, “Combining XenoTech’s ability to effectively elucidate metabolite formation through biological processes with the ability to efficiently produce milligram quantities of metabolites of interest for further evaluation is a benefit we must bring to our clients. By pairing XenoTech’s in vitro DMPK expertise with HepatoChem’s innovative platform, we are able to offer a tremendous and comprehensive solution to our customers for risk mitigation.”

The innovative technology uses biomimetic catalysts to mimic oxidative metabolism which synthesizes metabolites from the parent drug. The catalytic conditions are as selective as enzyme specificity achieved with microsomes or hepatocytes yet have the advantage of enabling metabolite production in milligram quantities. This unique system offers a highly competitive, higher-yield, cost-effective alternative to biological metabolite synthesis, facilitating knowledge early in the development process for informed program decision-making. Researchers around the world will benefit from this synergistic pairing of XenoTech’s distinguished expertise and holistic approach to drug metabolism research with HepatoChem’s unique, effective and efficient biomimetic oxidation platform. Biomimetic metabolite synthesis is now offered as both a service, with the work performed by the expert scientists at XenoTech and HepatoChem or for in-house work as a product, allowing customers the freedom to synthesize metabolites in their own laboratories via the BMO™ Kit.
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About XenoTech
XenoTech, LLC is a global Contract Research Organization with unparalleled experience and expertise in evaluating drug candidates, nutraceuticals, cosmetics, food additives and other compounds widely known as xenobiotics, substrates, inhibitors and inducers of cytochrome P450, UGT and other drug metabolizing enzymes and drug transporters. The company offers a variety of in vitro and in vivo safety assessment studies for drug candidate evaluation, as well as an extensive selection of products for drug metabolism research. XenoTech’s product selection includes a wide-range of high quality standard reagents, from subcellular fractions and hepatocytes to recombinant enzymes, substrates and metabolites. The company can also prepare and deliver custom-designed products and services in respnose to client requests. For additional information, please refer to the company’s website at www.xenotechllc.com or call (913) 438-7450.

About HepatoChem
HepatoChem, Inc. of Beverly, Massachusetts was founded in 2008, is a life science company that has developed its technology platform through a partnership with Princeton University. HepatoChem focuses on early stage development with a game-changing, proprietary chemistry platform that enables fast and cost-effective metabolite production from bioactive small molecules. The HepatoChem technology enables assessment of critical metabolite and toxicity issues early in the R&D continuum, reducing the risk of failure in clinical development of drug candidates. For more information, visit www.hepatochem.com