Use of Statistical Design of Experiments in the Optimization of Amide Synthesis Utilizing Polystyrene-Supported N-Hydroxybenzotriazole Resin

Journal of Combinatorial Chemistry

Volumn 4, Issue 6, 2002, Pages 576-583

  Gooding, Owen W ^a   Vo, Lanchi ^a   Bhattacharyya, Sukanta ^a   Labadie, Jeff W ^a  

^a Argonaut Technologies   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; POLYSTYRENE DERIVATIVE; RESIN; TRIAZOLE DERIVATIVE;

ARTICLE; CHEMISTRY; COMBINATORIAL CHEMISTRY; DRUG DESIGN; SYNTHESIS;

AMIDES; COMBINATORIAL CHEMISTRY TECHNIQUES; DRUG DESIGN; POLYSTYRENES; RESINS, SYNTHETIC; TRIAZOLES;

EID: 0036831648     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc0200282     Document Type: Article

References (22)

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3. This was the subject of a special feature section in a recent journal edition: Org. Process Res. Dev. 2001, 3, 272-339.
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8. Salvino, J. M., Kumar, N. V.; Orton, E. Airey, J.; Keisow, T.; Crawford, K.; Mathew, R. Krolikowski, P.; Drew, M.; Engers, D.; Krolikowski, D.; Herpin, T.; Gardyan, M.; McGeehan, G.; Labaudiniere, R. J. Comb. Chem. 2000, 2, 691-697. See refs 1-5.
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13. (b) Commercially available from Argonaut Technologies.
14. A preliminary account of this work was presented in part. Vo, L.; Bhattachayya, S.; Gooding, O. W.; Labadie, J. W. Abstracts of Papers, 222nd National Meeting of the American Chemical Society, Chicago, IL, 2001: American Chemical Society: Washington, DC, 2001.
15. Here, the loading refers to the efficiency of loading the acids onto the PS-HOBt resin to form the active esters.
16. The Fusion Pro package available from S-Matrix Corp. was used (www.s-matrix-corp.com).
17. The Trident synthesizer (Argonaut Technologies) was used in this work.
18. Resin loading refers to the efficiency of loading the acid onto the PS-HOBt resin. Because excess benzylamine was used, it was assumed that 100% of the loaded acid was released as benzylbenzamide.
19. We also found that order of addition was especially important when conducting larger scale reactions where active esters were prepared in bulk so that they could split out for subsequent reactions. In the case of 10 g and larger preparations, it was advantageous to allow the reaction mixtures to mix for 10-15 min prior to final addition of the carboxylic acid solution.
20. Response surface graphs could not be generated here because there is less than two continuous (numeric) variables.
21. In ref 7, Salvino et al. comment on the difficulty in forming active esters with substrates containing basic amine or phenylacetic acid.
22. 1H NMR spectra were obtained on 38% of the samples to confirm structural assignments. Because the compounds are known and amide synthesis via this methodology is well established, this was viewed as sufficient characterization.