Abstract
The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adams JH, Cook RM, Hudson D, Jammalamadaka V, Lyttle MH, Songster MF (1998) A reinvestigation of the preparation, properties, and applications of aminomethyl and 4-methylbenzhydrylamine polystyrene resins. J Org Chem 63:3706–3716
Bernatowicz MS, Daniels SB, Köster H (1989) A comparison of acid-labile linkage agents for the synthesis of peptide C-terminal amides. Tetrahedron Lett 30:4645–4648
Breitenstein W, Hayakawa K, Iwasaki G, Kanazawa T, Kasaoka T, Koizumi S, Matsunaga S, Nakajima M, Sakaki J (2001) Preparation of arylsulfonamido-substituted hydroxamic acid derivatives as MMP2 inhibitors. Int Pat Appl WO 2001010827
Chiu C, Tang Z, Ellingboe JW (1999) Solid-phase synthesis of 2,4,6-trisubstituted pyridines. J Comb Chem 1:73–77
Dyson RM, Helg AG, Meisenbach M, Allmendinger T (2000) In situ observation of the progress of a large-scale on-bead reaction. 11th International Symposium on Pharmaceutical and Biomedical Analysis, Basle, Switzerland, p 007
Felder ER, Marzinzik AL (1998) Key intermediates in combinatorial chemistry: access to various heterocycles from α,β-unsaturated ketones on solid phase. J Org Chem 63:723–727
Fréchet JMJ, Haque KE (1975) Use of polymers as protecting groups in organic synthesis. II. Protection of primary alcohol functional groups. Tetrahedron Lett 16:3055–3056
Fréchet JMJ, Nuyens LJ (1976) Use of polymers as protecting groups in organic synthesis. III. Selective functionalisation of polyhydroxy alcohols. Can J Chem 54:926–934
Graffner-Nordberg M, Sjödin K, Tunek A, Hallberg A (1998) Synthesis and enzymatic hydrolysis of esters, constituting simple models of soft drugs. Chem Pharm Bull 46:591–601
Harmon RE, Rizzo VL, Gupta SK (1970) Synthesis of 3-hydroxy-4-imidazolidinones. J Heterocyc Chem 7:439–442
Kaiser E, Colescott RL, Bossinger CD, Cook PI (1970) Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem 34:595–598
Lee S, Robinson G (1995) Process development: fine chemicals from grams to kilograms. Oxford University Press, Oxford
Meienhofer J, Waki M, Heimer EP, Lambros TJ, Makofske RC, Chang CD (1979) Solid phase synthesis without repetitive acidolysis. Preparation of leucyl-alanyl-glycyl-valine using 9-fluorenylmethyloxycarbonylamino acids. Int J Pep Prot Res 13:35–42
Meisenbach M, Voelter W (1997) New methoxy-substituted tritylamine linkers for the solid phase synthesis of protected peptide amides. Chem Lett 1265–1266
Meisenbach M, Allmendinger T, Mak CP (2003) Scale-up of the synthesis of a pyrimidine derivative directly on solid support. Org Proc Res Dev 7:553–558
Ohki H, Wada M, Akiba K (1988) Bismuth trichloride as a new efficient catalyst in the aldol reaction. Tetrahedron Lett 29:4719–4720
Prühs S, Dinter C, Blume T, Schütz A, Harre M, Neh H (2006) Upscaling the solid-phase synthesis of a tetrahydrocarbazole in chemical development. Org Proc Res Dev 10:441–445
Raillard SP, Ji G, Mann AD, Baer TA (1999) Fast scale-up using solid-phase chemistry. Org Proc Res Dev 3:177–183
Rink H (1987) Solid phase synthesis of protected peptide fragments using a trialkoxydiphenyl-methylester resin. Tetrahedron Lett 28:3787–3790
Yan B, Gremlich HU, Moss S, Coppola GM, Sun Q, Liu LJ (1999) Comparison of various FTIR and FT Raman methods: applications in the reaction optimisation stage of combinatorial chemistry. J Comb Chem 1:46–54
Zikos CC, Ferderigos NG (1995) Preparation of high capacity aminomethyl-polystyrene resin. Tetrahedron Lett 36:3741–3744
Author information
Authors and Affiliations
Corresponding author
Editor information
Rights and permissions
Copyright information
© 2007 Springer-Verlag
About this paper
Cite this paper
Meisenbach, M., Allmendinger, T., Mak, CP. (2007). Solid-Phase Supported Synthesis: A Possibility for Rapid Scale-Up of Chemical Reactions. In: Seeberger, P., Blume, T. (eds) New Avenues to Efficient Chemical Synthesis. Ernst Schering Foundation Symposium Proceedings, vol 2006/3. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2007_034
Download citation
DOI: https://doi.org/10.1007/2789_2007_034
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-70848-3
Online ISBN: 978-3-540-70849-0
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)