GRC_Poster_2015
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This poster presents a flow hydrogenation method for efficiently synthesizing 3D piperidine derivatives from aromatic precursors using a H-Cube flow reactor system. Various mono- and disubstituted pyridines and related nitrogen heterocycles were reduced under optimized conditions with good selectivity. Palladium on carbon was found to be the most effective catalyst. The reductions provided access to piperidine and related scaffolds with stereoselectivity in some cases. The developed continuous-flow process provides advantages over batch hydrogenation and allows for scale-up and incorporation into automated synthesis workflows.
GRC_Poster_2015
- 1. 0 10 20 30 40 50 60 70 80 90 100 0 500 1000 1500 Area % (220nm) t (min) Start. Mat. Product Side-‐Product Pressure-‐drop FLOW HYDROGENATION; A TOOL FOR CREATING 3D-‐ SHAPED MOLECULES FROM FLAT PRECURSORS David Gunn2, Laszlo Kocsis2, Szabolcs Fekete 1 , Janos Gerencser 1 , Gergely Makara 1 , Ferenc Darvas 1,2 1 ComInnex Inc., Záhony u. 7. H-‐1031 Budapest, Hungary, e-‐mail: fekete.szabolcs@cominnex.com 2 ThalesNano Inc., Záhony u. 7. H-‐1031 Budapest, Hungary In this poster we present the efficient and convenient flow synthesis of mono- and disubstituted piperidine derivatives from their aromatic precursors. Rapid catalyst and condition screening was done in the automated H-Cube® flow reactor system equipped with a CatCart Changer™ module. The optimized conditions were used as a general procedure to synthesize analogous structures using H-Cube Autosampler™. Diastereoselectivity in the reduction of disubstituted pyridine species has also been investigated. Introduction Due to high-throughput synthetic practices over the past decades the number of achiral, aromatic compounds tremendously increased in compound libraries. Too many aromatic rings present higher attrition rate in the drug pipeline, and the diversity of shapes in the set of known 2D-shaped drugs is extremely low,1 thus the need for the design and synthesis of non-flat molecules having more advantageous properties is increasing.2 Complexity as measured by fsp3 (fraction of sp3 carbons) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs.3 New 3D- shaped templates could easily be generated via simple reduction of flat aromatic precursors. Reduction is difficult to automate and it suffers from inconveniencies under batch conditions. This hurdle can be overcome by the use of flow hydrogenation reactors Results and Discussion Moderate conversion and/or product selectivity has been observed in the reduction of mono-substituted pyridines in ethylacetate and alcohols. The selectivity was increased in glacial acetic acid. This observation is in accordance with the theory claiming that the faster rate of hydrogenation could be due to flat absorption of the pyridinium ion on the catalyst surface, whereas the free base may absorb edgewise. Thus, all experiments were performed exclusively in glacial acetic acid in 0.02M concentration. Although vast variation of catalysts (Pd/C, PtO2, Pt/C, Rh/C, Ru/C, Pd(OH)2) were tested, finally 10% palladium on carbon was selected for further experiments due to better results achieved and cost saving considerations. Product selectivity was highly dependent on the applied temperature. The best product selectivity was obtained at 50 °C thus for further reductions these optimized conditions were applied. Effect of substitution was investigated among various mono substituted pyridines. No connection was observed between the rate of hydrogenation and the electronic character of the substituents. Conversion (%) Selectivity (%)Product Starting Material 0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 30 Area % (220nm) t (min) Start. Mat. Product Side-‐Product 0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 Area % (220nm) t (min) 50°C 100°C Although conversion got better the selectivity decreased 0.02M AcOH, 50 bar, 1mL/ min, Pd/C-10% (70mm) different temperatures Mono-substituted quinoline derivatives have also been readily saturated on palladium catalyst with very good selectivity. Sometimes reduction of these type of skeletons takes place under mild conditions. The investigation of the reduction of disubstituted quinoline analogues is in progress. Less bulky disubstituted pyridine derivatives could easily be saturated furnishing the desired piperidine derivatives. Reductions were done at elevated temperature (80 °C) on Pd/C catalyst with 100% conversion and excellent product selectivity. In most reductions a major stereoisomer was received in moderate to good stereoselectivity. The relative configurations were determined by 2D and 13C NMR experiments4. Conversion (%) Selectivity (%)Product Starting Material 1a 2a 3a 4a 100 100 100 100 90 85 95 65 a 0.04M AcOH solution, 50 bar, 80 °C, 70 mm Pd/C (10%) CatCart®, 1 mL/min a 0.02M AcOH solution, 50 bar, 50 °C, 70 mm Pd/C (10%) CatCart®, 1 mL/min. b Selectivity vs. over-saturated side-product. 1a 2a 3a 4a 5a 6a 7a 8a 9a 100 100 85 100 100 100 100 60 100 100 100 100 >95b >95b 100 100 100 100 Summary 1 S Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887. 2 Ritchie, T. J.; Macdonald, S. J. DDT, 2009 Nov, 14(21-22), 1011. 3 Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem., 2009, 52, 6752. 4 Díaz, J. L.;, C. Synth. Commun., 2008, 38, 2799-2813. Conversion (%) Selectivity (%)Product Starting Material 1a 2b 3c 85 70 100 good >95 >95 a 0.02M AcOH solution, 50 bar, 100 °C, 70 mm Pd/C (10%) CatCart®, 1 mL/min. b 0.02M AcOH solution, 50 bar, 50 °C, 70 mm Pd/C (10%) CatCart®, 1 mL/min. c 0.02M AcOH solution, atm. H2 pressure, 25 °C, 70 mm Pd/C (10%) CatCart®, 1 mL/min cis/trans (%) 100/0 60/40 70/30 80/20 Instrumentation The H-Cube® flow reactor system equipped with a CatCart Changer™ module was used for rapid solvent and catalyst screening. The reductions under the optimized conditions were done using the H-Cube Autosampler™ that provides all benefits of the H-Cube® integrated with a liquid handler. ThalesNano’s technology solutions for automated laboratories We have developed a convenient and general approach for the reduction of pyridine analogues in the H- Cube® flow hydrogenation system. The developed methods can easily be scaled up producing high fsp3 containing fragments and/or scaffolds from readily available simple flat aromatic compounds. All of the information received are stored in ComInnex’s electronic know-how database system that allows chemists to predict and evaluate overcome of hydrogenations. Reduction of bulky and flat diphenyl substituted pyridines furnished the desired products in low yields even under harsh conditions. Moderate hydrogenation rate enhancement could be reached only by increasing the temperature to 100 °C but no significant difference was observed when switching from palladium catalyst to the more active platinum. Among diphenylpyridine analogues slightly better hydrogenation rates have been observed for 3,5- and 3,4-dyphenylpyridines than for 2,4-, 2,5- and 2,6- diphenylpyridines. Disubstituted pyridines A 0.02M solution of 2-phenylpyridine was reduced in an H-Cube® flow system through a 70 mm long cartridge filled with ca. 250 mg catalyst. Noticeable activity decrease was observed after the reduction of ca. 4.5g material. Pressure deviance caused only by the HPLC pump. This good catalyst longevity makes the synthesis of fragment-like libraries cost-effective. Scale-up results References In the hydrogenation of mono- and di-substituted naphtpyridines on palladium catalyst the selectivity strongly depends on both the applied conditions and the substitution of the naphtpyridine’s skeleton. Hydrogenation rates could be promoted by the addition of TFA as an accelerator. ConditionsProduct(s) Starting Material A B 1a 2a 100 100 MeOH-TFA, 50 °C, 50 bar MeOH, 50 °C, 1 bar MeOH-TFA, 50 °C, 1 bar A B 0 26 74 40 60 AcOH, 80 °C, 50 bar a 0.02 M solution in specified solvent, 70 mm Pd/C (10%) CatCart®, 1 mL/min, 100% conversion was achieved in each. 100% 100% 100% 100% 100% 100% Aminopyrimidinesa Aminopyridinesa 2-Aminopyridines and aminopyrimidines have been hydrogenated to the appropriate amidine and guanidine derivatives on palladium catalyst with very good selectivity. Under general H-Cube® conditions the benzopyrimidine could be saturated selectively to imine drivative. The extension of the method to more complex N- heterocycles is under investigation. Preliminary results showed that the conditions presented in this poster can be applied successfully to other ring systems as well. a 0.02M AcOH solution, 50 bar, 50 °C, 70 mm Pd/C (10%) CatCart®, 1 mL/min. ComInnex’s Know-‐How Effect of substitution