Removing Ru from metathesis reactions

September 25th, 2017 Leave a reply »

Removing residual ruthenium down to levels acceptable for pharma has been recently reviewed by Wheeler and coworkers at Materia [1], using both extractive and adsorptive methodology, and by the Fogg group [2].  For Ru the key consideration is to control the amount of residual Ru at a permissible daily exposure limit (PDE) in the drug substance of NMT 100 micrograms / day, if given orally [3].  In addition, it is necessary to control the amount of residual reagent in the product, so a convenient assay for any reagent used is desirable.  For operations on scale inexpensive and readily available reagents are desirable, and purification should be performed without preparative chromatography.

There are three main approaches to removing metal compounds [4].  These approaches include precipitating or crystallizing the metal impurities, solubilizing metal species away from the drug substance (including crystallizing the API or intermediate), or adsorbing metal species onto an insoluble reagent.  General approaches are to prepare an insoluble metal salt such as an oxalate and remove it by filtration [5] or to treat a reaction mixture with trimercaptotriazine to precipitate divalent metal species [6, 7].  Dithiocarbamates have also been found to effectively remove Ru by precipitation [8].  2-Mercaptonicotinic acid [9] and imidazole [10] have been used to quench metatheses and to extract the Ru species away from the products of metathesis; these reagents have chromophores that could permit ready quantitation of residues in the API by HPLC.  Treatment with an aqueous solution of cysteine has removed Ru from a process stream [11]; since cysteine is an essential amino acid, permissible levels of this contaminant in an API should be fairly high.  Ethylene diamine has been added to quench a RCM and remove Ru [12].  Controlling the pH may be critical for using any aqueous solution.  For the third approach, hydrogenation can remove Ru, probably by adsorption of the Ru hydride species [13] to the activated carbon provided with a Pd/C catalyst [14].  Treatment with activated carbon, such as Ecosorb® 908, has also been effective [15].  Polymeric scavenging reagents may sequester Ru species; a consideration with polymeric reagents is that over time the metal species can leach from the resin (“break through”). When optimizing processes it is helpful to remember that by minimizing the charge (wt/wt) of the metal-containing reagents the burden of removing related impurities can be reduced.

Tris(hydroxymethyl)phosphine has been used to remove Ru from intermediates for drug substances, but for pharma some caution is due.  In 1999 the Grubbs group applied this reagent for removing Ru species, using 10 or more equivalents of P(CH2OH)3 [16]; in other cases, 25 or more  equivalents have been required for efficient removal of Ru [17].  At a catalyst loading of 5 mol%, for instance, 1.25 equivalents of P(CH2OH)3 relative to starting material might be required, and even with the high solubility of P(CH2OH)3 in water complete removal of the reagent might be difficult.  Treatment of the less expensive tetrakis(hydroxymethyl)phosphonium chloride [18] with aqueous NaOH generated P(CH2OH)3, HCHO, and a N-methylol impurity of a secondary amide [11].  As an alkylating agent the latter could be flagged by regulatory authorities as a potential mutagenic impurity [19].  P(CH2OH)3 is a P-methylol and could also be flagged as a potential mutagenic impurity.  No mutagenicity or carcinogenicity data have been reported for P(CH2OH)3 [20].  The reactivity of P(CH2OH)3 towards amines has been documented: in 1999 P(CH2OH)3 was shown to react with glycine in H2O at RT to form the tris glycine adduct P(CH2NHCH2CO2H)3 [21], and P(CH2OH)3 has been used to crosslink polypeptides in aqueous solution [22].  Since many drug candidates are amines, some impurities could be generated upon contact with P(CH2OH)3.  Because P(CH2OH)3 has no strong chromophore, detection and quantitation of residual P(CH2OH)3 may be difficult by HPLC with standard UV detectors, and detection by GC may require derivatization.  Hence researchers in pharma may prefer to avoid using P(CH2OH)3 for removing metal ions near the end of a route to prepare a drug substance.

As indicated in the paragraph above, many reagents that have been developed and employed for removing Ru are not amenable for preparing APIs on scale, but others may have promise.  For instance, the Paquette group published that addition of Pb(OAc)4 (1.5 eq. relative to the Grubbs catalyst) removed colored byproducts from metathesis [23]; most researchers in pharma will not want to complicate their workups by adding Pb to the reaction streams.  Ethyl 2-isocyanoacetate and potassium 2-isocyanoacetate have been used to quench metatheses, but plug chromatography was required [24] and these reagents are relatively expensive .  Diethylene glycol monovinyl ether also efficiently quenches metatheses, but silica gel purification was required to remove the Ru species [25]; this reagent is relatively inexpensive, and might find adaptation for pharma.

I thank Dr. Philip Wheeler and Dr. David Snodin for helpful discussions.

References

  1. Wheeler, P.; Phillips, J. H.; Pederson, R. L. Process Res. Dev. 2016, 20, 1182.
  2. Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Chem. Int. Ed. 2016, 55, 3552.
  3. ICH Q3D Guideline for Elemental Impurities, December 2014: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf
  4. Anderson, N. G., Practical Process Research & Development – A Guide for Organic Chemists; 2nd edition; Academic Press: San Diego; 2012; Chapter 11.
  5. For example, Cu(II) can be removed by filtration as the oxalate: Sedergran, T. C.; Anderson, C. F. US 4,675,398, 1987 (to E. R. Squibb & Sons). Oxalate salts have also been effective for removing Pd.
  6. Rosso, V. W.; Lust, D. A.; Bernot, P. J.; Grosso, J. A.; Modi, S. P.; Rusowicz, A.; Sedergran, T. C.; Simpson, J. H.; Srivastava, S. K.; Humora, M. J.; Anderson, N. G. Process Res. Dev. 1997, 1, 311.
  7. Malmgren, H.; Bäckström, B.; Sølver, E.; Wennerberg, J. Process Res. Dev. 2008, 12, 1195.
  8. Gallagher, W. P.; Vo, A. Process Res. Dev. 2015, 19, 1369.
  9. Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.;Ridges, M. D.; Spinelli, E. M.; Johnson, M. J. Org. Chem. 2006, 71, 7133.
  1. Brenner, M.; Meineck, S.; Wirth, T. U.S. Patent 7,183,374 B2, 2007 (to Boehringer Ingelheim).
  2. Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S. N.; Ouyang, X.; Clark, W. M., Jr. Tetrahedron 2009, 65, 6291.
  3. Puentener, K.; Scalone, M. US 7939668B2, 2011 (to Roche Palo Alto LLC).
  4. Louie, J.; Bielawski, C. W.; Grubbs, R. H. Am. Chem. Soc. 2001, 123, 11312.
  5. Wang, H., in Transition Metal-Catalyzed Couplings in Process Chemistry; Magano, J.; Dunetz, J. R., Eds.; Wiley – VCH; 2013; pp. 233-251; Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M., Jr. Process Res. Dev. 2008, 12, 226.
  6. Welch, C. J.; Leonard, W. R.; Henderson, D. W.; Dorner, B.; Childers, K. G.; Chung, J. Y. L.; Hartner, F. W.; Albanese-Walker, J.; Sajonz, P. Process Res. Dev. 2008, 12, 81.
  7. Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
  8. Pederson, R. L.; Fellows, I. M.; Ung, T. A.; Ishihara, H.; Hajela, S. P. Synth. Catal. 2002, 344, 728.
  9. Safety note: in water, decomposition of this phosphonium chloride may generate phosphine (PH3) in addition to HCHO and HCl: https://pubchem.ncbi.nlm.nih.gov/compound/Tetrakis_hydroxymethyl_phosphonium_chloride
  10. ICH M7 Guidance, May 2015: http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm347725.pdf
  11. LD50 Oral – rat – 178 mg/kg: http://img1.guidechem.com/msdspdf/2767-80-8.pdf
  12. Berning, D. E.; Katti, K. V.; Barnes, C. L.; Volkert, W. A. J. Am. Chem. Soc. 1999, 121, 1658.
  13. Lim, D. W.; Nettles, D. L.; Session, L. A.; Chilkoti, A. Biomacromolecules 2007, 8, 1463.
  14. Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.; Méndez-Andino, J.; Yang, J. Lett. 2000, 2, 1259.
  15. Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.; Diver, S. T. Org. Lett. 2007, 9, 1203.
  16. Liu, W.; Nichols, P. J.; Smith, N. Tetrahedron Lett. 2009, 50, 6103.

 

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