Scale-up examples

  • The selected examples have been divided into reaction class
  • A scavenger/removal method may be applicable to other reaction classes
  • In most cases, a residual metal analysis has been reported. A not given value means none was reported in the paper (although metal purging was deemed necessary), so it can be assumed the metal content is below the level of regulatory concern.
  • The solvent given is, as far as can be determined from the experimental given, the mix used in the metal removal process and not always the solvent(s) used in the metal-catalysed reaction.
  • In most examples, the metal is removed as part of the work-up immediately following the metal-catalysed reaction, although in some cases the metal maybe purged further downstream in the synthetic route.

Relevant scale up examples – Suzuki

Reference Scale Solvent Catalyst Removal method Residual metal
OPRD, 2008, 12, 896 1Kg IPA-H2O-Toluene Pd(OAc)2  (o-Tol)3P NaHSO3 aq wash 100ppm Pd
OPRD, 2009, 13, 268 50 g t-BuOH-H2O Pd/C (heterogeneous) Recryst MeOH-water <20 ppm Pd
OPRD, 2015 19, 721 7 kg iPrOAc (Ph3P)2PdCl2 3- mercaptopropyl ethyl sulfide silica  SPM-32 from PhosphonicS <0.2 ppm Pd
OPRD, 2013, 17, 359 30 g Dioxane-EtOAc PdCl2DPPF Citric acid aq 0.1 ppm Pd
OPRD, 2013, 17, 413 1.5 kg Toluene Pd(OAc)2/ DPPF thiolized silica gel (Silicycle) 46 ppm Pd
OPRD, 2007, 11, 951 8 kg IPA-H2O PdCl2DPPF.CH2Cl2 Et3N 8 ppm Pd
OPRD, 2010, 14, 263 3 kg EtOAc-THF Pd2(DBA)3/t-Bu3PHBF4 Arbocel filter aid then Darco KB (carbon) 4 ppm Pd
OPRD, 2010, 14, 417 10 g 2-MeTHF [C5H4P(t-Bu)2]FePdCl2 Filterol GR then Silicycle 3-mercaptopropyl functionalized silica 4 ppm Pd
OPRD, 2013, 17, 97 100 g DCM (Ph3P)2PdCl2 Florisil (60−100 mesh then Thio-silica Not given
OPRD, 2013, 17, 97 48 kg MeCN Ni(NO3)26H2O/ Ph3P Aqueous NH3 Not given
OPRD, 2007, 11, 1051 150 g Dioxane-EtOAc Pd(OAc)2/ Ph3P n-Bu3P <10 ppm Pd
OPRD, 2007, 11, 985 8.5 kg iPrOAc (Ph3P)4Pd Picachem carbon 80PN <50 ppm Pd
OPRD, 2006, 10, 512 4 kg Acetone Pd(OAc)2/ Ph3P Deloxan resin (Thiourea-Functionalized Polysiloxane) 20-40 ppm
OPRD, 2005, 9, 621 630 g MeOH-H2O Palladium black (heterogenous) Hyflo Super-Cel 3-8 ppm Pd
OPRD, 2003, 7, 191 4.5 kg toluene (Ph3P)2PdCl2 DIAION CR20 (polyamino functionalised resin) 35 ppm Pd
OPRD, 2001, 5, 450 500 g THF-EtOAc-H2O (Ph3P)4Pd Trithiocyanuric acid Not given
OPRD, 2011, 15, 1018 50 kg Toluene-H2O DPPF.PdCl2 15% Cystine on SiO2 13 ppm Pd
OPRD, 2010, 14, 1438 18 kg Heptane (Ph3P)4Pd SiO2 Not given
OPRD, 2010, 14, 883 70 g H2O [t-Bu3PPdBr]2 SMOPEX110 ≤1 ppm Pd
OPRD, 2010, 14, 849 3 kg DMF Pd(PtBu3)2 Ecosorb C-941 then MP-TMT resin 7 ppm Pd
OPRD, 2009, 13, 1419 22 kg EtOAc-EtOH [C5H4P(t-Bu)2]FePdCl2 Filterol GR then Acticarbone CPL carbon 5 ppm Pd
OPRD, 1999, 3, 248 6 kg MeOH-H2O Pd/C (heterogeneous) Celite <6 ppm Pd
OPRD, 2014, 18, 646 3 kg Butanone Pd-118 catalyst = C5H4P(t-Bu)2]FePdCl2 Quadrasil MP Propanethiol silica resin <50 ppm Pd
OPRD, 2013, 17, 846 400 g Toluene (Ph3P)2PdCl2 ISOLUTE Si-Thiol None detected
OPRD, 2008, 12, 637 20 kg NMP Pd(OAc)2 (o-Tol)3P Treatment of crude product with DPPE/1,2 Diaminopropane 5 ppm Pd
OPRD, 2015 19, 721 13kg MeCN Pd(OAc)2 ammonium pyrrolidine dithiocarbamate < 10 ppm Pd
OPRD, 2011, 15, 1124 1.5 kg MeCN-EtOAc Pd(OAc)2 (o-Tol)3P Carbon Darko KB wet powder 100 mesh  then and Arbocel/SiO2 Not given
OPRD, 2009, 13, 1130 87 kg Toluene Ph3P/PdCl2 TMT 15 ppm Pd
 OPRD, 2009, 13, 1130 10 g EtOH Pd(OAc)2 DPPE N-acetylcysteine/ NaOH aq 8 ppm Pd
OPRD, 2014, 18, 266 40  kg NMP-THF [Pd2(dba)3 / Xantphos 1,2-diaminopropane < 20 ppm Pd
OPRD, 2006, 10, 493 1 kg EtOH-HCl-H2O (Ph3P)2PdCl2/CuI Deloxan-THP 20 ppm Pd 2 ppm Cu
OPRD, 2009, 13, 598                                 25 g iPrOAc (Ph3P)4Pd/CuI SilicaBond-Thiol then Norit A supra 120 ppm Pd 20 ppm Cu
OPRD, 2003, 7, 733                      110 g Toluene-EtOH (Ph3P)2PdCl2/ Ph3P/CuI N-acetylcysteine 7 ppm Pd 1 ppm Cu
OPRD, 2015, 19, 721                            13kg THF (PhCN)2PdCl2/ tBu3P/CuI ammonium pyrrolidine dithiocarbamate < 10 ppm Pd < 10 ppm Cu
OPRD, 2012, 16, 1854 2.3 kg NMP (Ph3P)2PdCl2/CuI Cystine aq then NH4OH aq 25 ppm Pd
OPRD, 1997, 1, 294              0.4 kg DCM-Heptane (Ph3P)2PdCl2/CuI Norit A carbon < 20 ppm Pd < 20 ppm Cu
OPRD, 2001, 5, 383             50  kg MeOH-THF (Ph3P)2PdCl2/CuI Norit SX+ carbon 1.6 ppm Pd < 7 ppm Cu
OPRD, 2012, 16, 1811  0.5 kg iPrOAc Pd2(DBA)3 DPFF DARCO KB-G (activated carbon) 20-40 ppm Thio ether
OPRD, 2008, 12, 1201 150 g 2-MeTHF Pd(DBA)2 / Solka Floc then MP-TMT resin 37 ppm Pd amination
OPRD, 2013, 17, 672 65 g EtOH Pd(OAc)2/ BINAP Recryst from EtOH < 10 ppm Pd amination
OPRD, 2015 19, 721 20 kg EtOH-KOH-H2O CuI/N,N-1,2-dimethylcyclo hexane ammonium pyrrolidine dithiocarbamate < 10 ppm Cu Ullmann Coupling
OPRD, 2014, 18, 1752 1.5 kg THF Pd(DBA)2 / BINAP Magnesol (Mg silicate)/ Solkafloc (cellulose) then thiol-capped silica gel 73 ppm Pd amination
OPRD, 2012, 16, 1739 100 g DCM-H2O Pd(OAc)2/ BINAP trithiocyanuric acid/ NaHCO3/ activated charcoal 20 ppm Pd amination
OPRD, 2012, 16, 1787 3.5 kg Dioxane –H2O-Heptane CuI/DMEDA NH4Cl then NH4OH 14 ppm Cu Ullman coupling
OPRD, 2012, 16, 1811 0.5 kg i-PrOAc Pd2(DBA)3 DPFF DARCO KB-G (active carbon) 20-40 ppm Thio ether
OPRD, 2012, 16, 605 3.5 kg Toluene PdCl2 DPPF MP-TMT resin (Biotage Ltd.) 11 ppm Pd amination
OPRD, 2012, 16, 70–81 33 kg Xylene Pd2(DBA)3 XantPhos mercaptopropyl-functionalized silica gel (silicycle) Not given amination
OPRD, 2011, 15, 1046  26 kg THF PdCl2 DPPF SiliaBond thiol (Silicycle Inc) Not given Thio ether
OPRD, 2011, 15, 1052  2.5 kg DCM pentamethylcyclopentadienyliridium( III) chloride dimer Darco KBB Not given Borrow-odding hydrogen
OPRD, 2010, 14, 895  10 kg DMSO-MeOH CuI/N,N-dimethylglycine N,N-dimethylglycine 1 ppm Ullman coupling
OPRD, 2008, 12, 411  9 kg Pyridine -hexanes CuI NH4Cl aq then NH4OH aq Not given Ullman ether coupling
OPRD, 2011, 15, 44 10 kg DMSO-iPrOAc CuI L-cysteine aq Not given Ullman coupling
OPRD, 2010, 14, 346 400 g EtOH-H2O Cu2O/CuBr Na2S then charcoal < 20 ppm Cu Ullman thioether
OPRD, 2015, 19, 476 7  kg Toluene-MeOH Pd(OAc)2/ BrettPhos Silicyle-Thiourea resin < 2 ppm Pd Amination
OPRD, 2014, 18, 215 120 g DMAc CuBr/8-hydroxyquinoline Citric acid aq. Not given Ullman coupling
OPRD, 2014, 18, 205 1.5 kg THF CuI/ 2,2’ bipyridine EDTA aq. ~ 15 ppm Cu Ullman coupling
OPRD, 2014, 18, 501 90 kg DMF-2-MeTHF CuCl 30% H2O2 then citric aid aq. Not given Ullman coupling
OPRD,  2011, 15, 367–375 6 kg DMF-THF CuI N,N Dimethylethanediamine the HCl aq Not given Ullman coupling
OPRD, 2010, 14, 939 9 kg MeOH (Ph3P)2PdCl2/Ph3P Polystyrene-TMT 3 ppm Allyl group cleavage  
OPRD, 2012, 16, 63 0.7 kg Acetone (C3H5Pd)2/ SL-T002-1 SiO2 filtration Not given Chiral allyation
OPRD, 2012, 16, 129 4 kg toluene Pd2(DBA)3/t-Bu3PHBF4 Citric acid aq then Charcoal Not given Malonate α-arylation
OPRD, 2015, 19, 661 5 kg EtOAc Pd(OAc)2/ DPPF/ Zn Citric acid aq then Florisil Silicycle (Si-Thiol < 3ppm Pd < 3ppm Zn cyanation
OPRD, 2013, 17, 651 175 g iPrOAc (Ph3P)2PdCl2 N-Acetylcystine/ water 6 ppm Pd 20 ppm Zn Negishi coupling
OPRD, 2008, 12, 411 5 kg Hexanes CuI/Pyridine NH4Cl wash then NH4OH wash Not given Ether synthesis
OPRD, 2012, 16, 1832 80 kg Heptane Pd(OAc)2/ DPEphos 2-Mercapto benzoate aq the SiO2 Not given ketone α-arylation
OPRD, 2012, 16, 595 35 kg iPrOAc CuI/ DMEDA 10% citric acid aq Not given Cu catalysed cynation
OPRD, 2011, 15, 1124 150 g EtOAc  [Rh-(1,5COD)(S,S-Et-FerroTANE)]BF4 SiliaBond thiol (Silicycle Inc) Not given Chiral hydrogenation
OPRD, 2008, 12, 496 27 kg THF-H2O  [Rh(COD)Cl]2 / (R)-BI Smopex234 after oxone treatment 30 ppm Rh Chiral 1,4 alkylation
OPRD, 2007, 11, 237 65 g THF-DCM  Pd(PPh3)4 EDTA aq then thiol-modified silica / Kieselgel 60 <5 ppm Pd <5 ppm Zn Negishi coupling
OPRD, 2006, 10, 285   1 kg HCl-water (Ph3P)2PdCl2 Washing ppt with EDTA aq 20 ppm Pd Negishi coupling
OPRD, 2008, 12, 540   7 kg DMF [t-Bu3PPdBr]2 SiliaBond Thiol (Silicycle) then EDTA aq <2 ppm Pd Cyanation
OPRD, 1998, 2, 71         45 kg DCM CuCl chromatography on γ-alumina AC-12 Not given Ullman ether synthesis
OPRD, 2006, 10, 70   7 kg H2O/EtOH Pd(PPh3)4 Ethylene diamine aq then N-acetylCysteine/EDTA aq <1 ppm Pd <1 ppm Zn Negishi coupling
OPRD, 2010, 14, 1221 3 kg TBME DPPF.PdCl2 Cuno zetapad <10 ppm Pd Cyanation
OPRD, 2013, 17, 382 2.5 kg NMP-MeOH Pd(OAc)2/ DPPP N-acetyl-L-cysteine 4 ppm Pd Carbonylation
OPRD, 2013, 17, 838 1 kg MeOH-THF Pd/C SiliaBond DMT < 10 ppm Pd Debenzylation
OPRD, 2013, 17, 1561 12 kg DMF CuCN N-(2hydroxyethyl) ethylenediamine triacetic acid aq. Not given Cyanation
OPRD, 2014, 18,  693 160 kg i-PrOH Pd(OAc)2/ (o-Tolyl)3P N-methyl thiourea Not given Cyanation
OPRD, 2014, 18, 135 140 kg EtOH [(S)-BINAP-RuCl(benzene)]Cl SiliaMetS thiol <10 ppm Ru Chiral hydrogenation
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