Process Presentations

Improved Synthesis and Industrial Process Development of a-Phenyl-N-Butylnitrone

Credit: Sangeeta Baruah, Danie Hechter, Hannes Malan and Mukut Gohain

Sangeeta Baruah,1 Danie Hechter,2 Hannes Malan1* and Mukut Gohain1* Research and Development Department, Chemical Process Technologies, Pretoria, South Africa;1 Engineering Department, Chemical Process Technologies, Pretoria, South Africa.2 hannes@chemprotech.co.za; mukut@chemprotech.co.za Nitrone compounds are well known for their free radical trapping ability and the widespread use as spin traps in the electron paramagnetic resonance (EPR) spin trapping technique.1 One of the most commonly used nitrone spin traps is α-phenyl-N-tert-butylnitrone (PBN).2 The title compound (3) is synthesised by the reaction of benzaldehyde (1) with 2-methyl-2-nitropropane (2) in the presence of zinc dust and acetic acid in an appropriate alcoholic solvent.3 The reaction was found to be temperature sensitive, performing well between 10 - 20°C. Exceeding 20°C resulted in the formation of impurities and poor yields, while temperatures below 10°C resulted in extended reaction times along with incomplete conversion, also leading to poor yields. An efficient, atom economical process technology for the manufacture of PBN (3) at industrial scale in order to meet the demand of the South African market was successfully developed. Scheme 1: Synthesis route to PBN (3) 1) Durand, G.; Polidori, A.; Ouari, O.; Tordo, P.; Geromel, V.; Rustin, P.; Pucci, B. J. Med. Chem., 2003, 46, 5230. 2) Gautheron-Chapoulaud, V.; Pandya, S.U.; Cividino, P.; Masson, G.; Py, S. and Vallée, Y. Synlett, 2001, 8, 1281. 3) Calder, A.; Forrester, R. and Hepburn, P.S. Org. Synth., 1988, 6, 803. 4) CPT management and QC department. Critical Parameters • Proper mixing of reagents and substrates. • Temperature control during the reaction. Process Description: Reactors cleaned and prepared. Benzaldehyde (1) and 2-methyl-2- nitropropane (2) charged to the reactor containing alcohol. Agitator switched on. Zinc powder charged to the reactor via manhole. Water charged into the reactor. Close the reactor and ensure the vent is open. Acetic acid pumped into the reactor within 70-75 minutes. After completion of the reaction, discharge the reaction mixture into a new polypropylene drum. Store the reaction mixture at 5 °C for 24 hours. Filter out the zinc acetate. The filtrate is distilled. Appropriate solvent charged to crystallise out the pure PBN (3). Process Challenges • Zn removal from the final product to below 5 ppm. • Crystallisation to obtain commercial standard PBN (3). Conclusion: An industrial process technology for the commercial, large scale production of PBN (3) was developed.

Green Synthesis and Industrial Process Development of Cloprop

Credit: Chantal Scholtz, Danie Hechter, Hannes Malan and Mukut Gohain

Chantal Scholtz,1 Danie Hechter,2 Hannes Malan1* and Mukut Gohain1* Research and Development Department, Chemical Process Technologies, Pretoria, South Africa;1 Engineering Department, Chemical Process Technologies, Pretoria, South Africa.2 hannes@chemprotech.co.za; mukut@chemprotech.co.za Cloprop is an important biologically active compound belonging to the phenoxypropionic class of compounds.1 Cloprop is used as a growth regulator for pineapples, plums, peaches etc. and is extremely important for the South African agricultural sector. The title compound (3) is synthesised by the reaction of m-chlorophenol (1) and betachloropropionic acid (2) in the presence of a base such as NaOH, Na2CO3, KOH etc.2,3 A commercial process technology to manufacture cloprop (3) with a commercial standard purity of 99.5% has been developed. Reaction in organic solvents such as DMF, DMSO etc. resulted in difficult to remove impurities. The use of an aqueous reaction solvent resulted in fewer impurities which were easily removed by means of a mixed solvent slurry wash using water and an appropriate alcohol in a particular ratio. The only byproducts formed during the work-up protocol are NaCl and Na2SO4, which can be used in-house or for landfill. Scheme 1: Synthesis route to Cloprop (3) 1) Meng, X.-Q.; Zhang, J.-J.; Liang, X.-M.; Zhu, W.-J.; Dong, Y.-H.; Wu, X.-M.; Huang, J.-X.; Rui, C.-X.; Fan, X.-L.; Chen, F.-H. and Wang, C.-Q. J. Agric. Food Chem., 2009, 57, 610. 2) Sun, Z.; Khan, J.; Makowska-Grzyska, M.; Zhang, M.; Cho, J.H.; Suebsuwong, C.; Vo, P.; Gollapalli, D.R.; Kim, Y.; Joachimiak, A.; Hedstrom, L. and Cuny, G.D. J. Med. Chem., 2014, 57, 10544. 3) Gualtieri, F.; Bottalico, C.; Calandrella, A.; Dei, S.; Giovannoni, M.P.; Mealli, S.; Romanelli, M.N.; Scapecchi, S.; Teodori, E.; Galeotti, N.; Ghelardini, C.; Giotti, A. and Bartolini, A. J. Med. Chem., 1994, 37, 1712 4) CPT management and QC department. What R&D does • Study literature • Select suitable synthetic route • Develop method suitable for plant • Optimise synthesis • Characterise fully • Scale-up synthesis • Process development • Process troubleshooting Important Considerations • Cost • Simplicity • Availability of reagents • Scalability and practicality • Time • Polymorphism • Waste • Safety Process Challenges • Temperature control • pH control • Recrystallisation • Removal of impurities • Minimising product loss • Minimising waste produced Process Chemistry: Phenol converted to sodium phenoxide followed by SN2 nucleophilic substitution reaction (Williamson ether synthesis) resulting in formation of the sodium salt. Acidification protonates the molecule resulting in its precipitation from the aqueous medium for easy filtration. Process Description: Reactors cleaned and prepared. 3-chlorophenol (1) warmed in a steam bath. Water charged into the reactor, switch on agitator and cooling applied. Aq. NaOH charged. 3-Chlorophenol (1) charged. 2-Chloropropionic acid (2) added slowly via glass dosing vessel. Reactor heated for ±4h. pH monitored carefully. On completion of reaction reactor is cooled. Reaction neutralised with aq. H2SO4 to pH 1.5. Reaction media transferred to glass-lined reactor for precipitation then transferred to filtration unit. Reaction filtered followed by slurry heat wash, hot filtration and recrystallisation to obtain >99.5 %purity. Conclusion: An industrial process technology for the commercial, large scale production of Cloprop (3) in >99.5% purity was developed.

Improved Synthesis and Industrial Process Development of the Sodium Salt of 2,3 Dimercapto-1-Propanesulfonic Acid (Na-DMPS)

Credit: Pfano Phungo, Isaac Mudau, Danie Hechter, Hannes Malan and Mukut Gohain

Pfano Phungo,1 Isaac Mudau,1 Danie Hechter,2 Hannes Malan1* and Mukut Gohain1* Research and Development Department, Chemical Process Technologies, Pretoria, South Africa;1 Engineering Department, Chemical Process Technologies, Pretoria, South Africa.2 hannes@chemprotech.co.za; mukut@chemprotech.co.za 2,3-Dimercapto-1-propanesulfonic acid (DMPS) and its sodium salt (2, Na-DMPS) are chelating agents that form complexes with various heavy metals.1 The sodium salt of DMPS was found to be effective in lowering the body burden of mercury and in decreasing the urinary mercury concentration to normal levels.2 Na-DMPS is synthesised by reaction of allyl bromide (1) with sodium sulfite followed by bromination using molecular bromine under aqueous conditions. This is followed by reaction with sodium sulfide in acidic medium to form the dithiol of the corresponding sulfonic acid sodium salt. The formed sulfonic acid sodium salt is recovered from water by complexation with appropriate metal salts such as FeCl3, ZnCl2, lead acetate etc. After recovering the sulfonic acid sodium salt as a metal-thio complex it is reacted with HCl or H2S in alcoholic solvent resulting in the respective metal precipitating out as its sulfide, which is removed by means of vacuum filtration. The required unithiol could then be recovered from the filtrate by means of a specifically designed process. Scheme 1: Synthesis route to Na-DMPS (2) 1) Hruby K; Donner, A. Medical Toxicology, 1987, 2, 317. 2) Aposhian, HV. Annu. Rev. Pharmacol. Toxicol., 1983, 23, 193. 3) CPT management and QC department. Reaction Scheme Process Description: Reactors cleaned and prepared. Charge water and Na2SO3, heat. Charge 1 slowly via glass dosing vessel. Heat for ±6 h. Extract, aq. layer collected. Unreacted 1 removed by vacuum distillation. Charge bromine slowly via glass dosing vessel. Unreacted bromine removed via vacuum. Charge water and NaSH. Charge HCl (aq.). Adjust pH, filter under vacuum. Charge lead acetate solution. Hot filter. Slurry heat wash, filter and dry. Suspend in MeOH, pass H2S gas generated in-situ from NaSH and HCl followed by filtration. Adjust pH and filter to obtain 2. Filtrate distilled and solid re-enters cycle at addition of NaSH and HCl (aq.). Process Challenges • Bromination and working with bromine. • Generating H2S (g) in-situ. • Scrubbing H2S (g) from the reaction. • Removing lead from the reaction products. • Recrystallisation Conclusion: An industrial process technology for the commercial, large scale production of Na-DMPS (2) was developed.