Automated synthesis and purification of amides: Exploitation of automated solid phase extraction in organic synthesis

Synthesis

Volumn , Issue 5, 1997, Pages 553-558

  Lawrence, R Michael ^a   Biller, Scott A ^a   Fryszman, Olga M ^a   Poss, Michael A ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE;

ARTICLE; COUPLING FACTOR; DRUG PURIFICATION; DRUG SYNTHESIS; NONHUMAN; PEPTIDE SYNTHESIS; SOLID PHASE EXTRACTION; STRUCTURE ANALYSIS;

EID: 0030973401     PISSN: 00397881     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-1997-1232     Document Type: Article

References (31)

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4. Lam, D. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmicrski, W. M.; Knapp, R. J. Nature 1991, 354, 82. Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84. Geysen, H. M.; Mason, T. J. Bioorg. Med. Chem. Lett. 1993, 3, 397. Houghten, R. A.; Dooley, C. T. Bioorg. Med. Chem. Lett. 1993, 3, 405. Kerr, J. M.; Banville, S. C.; Zuckermann, R. N. J. Am. Chem. Soc. 1993, 115, 2529. Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am. Chem. Soc. 1992, 114, 10646. Bunin, B. A.; Ellmann, J. A. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
5. Lam, D. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmicrski, W. M.; Knapp, R. J. Nature 1991, 354, 82. Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84. Geysen, H. M.; Mason, T. J. Bioorg. Med. Chem. Lett. 1993, 3, 397. Houghten, R. A.; Dooley, C. T. Bioorg. Med. Chem. Lett. 1993, 3, 405. Kerr, J. M.; Banville, S. C.; Zuckermann, R. N. J. Am. Chem. Soc. 1993, 115, 2529. Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am. Chem. Soc. 1992, 114, 10646. Bunin, B. A.; Ellmann, J. A. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
6. Lam, D. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmicrski, W. M.; Knapp, R. J. Nature 1991, 354, 82. Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84. Geysen, H. M.; Mason, T. J. Bioorg. Med. Chem. Lett. 1993, 3, 397. Houghten, R. A.; Dooley, C. T. Bioorg. Med. Chem. Lett. 1993, 3, 405. Kerr, J. M.; Banville, S. C.; Zuckermann, R. N. J. Am. Chem. Soc. 1993, 115, 2529. Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am. Chem. Soc. 1992, 114, 10646. Bunin, B. A.; Ellmann, J. A. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
7. Lam, D. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmicrski, W. M.; Knapp, R. J. Nature 1991, 354, 82. Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84. Geysen, H. M.; Mason, T. J. Bioorg. Med. Chem. Lett. 1993, 3, 397. Houghten, R. A.; Dooley, C. T. Bioorg. Med. Chem. Lett. 1993, 3, 405. Kerr, J. M.; Banville, S. C.; Zuckermann, R. N. J. Am. Chem. Soc. 1993, 115, 2529. Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am. Chem. Soc. 1992, 114, 10646. Bunin, B. A.; Ellmann, J. A. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
8. Lam, D. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmicrski, W. M.; Knapp, R. J. Nature 1991, 354, 82. Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84. Geysen, H. M.; Mason, T. J. Bioorg. Med. Chem. Lett. 1993, 3, 397. Houghten, R. A.; Dooley, C. T. Bioorg. Med. Chem. Lett. 1993, 3, 405. Kerr, J. M.; Banville, S. C.; Zuckermann, R. N. J. Am. Chem. Soc. 1993, 115, 2529. Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am. Chem. Soc. 1992, 114, 10646. Bunin, B. A.; Ellmann, J. A. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
9. Manipulation of heterogeneous mixtures by robotic systems results in clogging of the liquid flow paths.
10. Wetterau, J. R.; Sharp, D. Y.; Gregg, R. E., Biller, S. A.; Dickson, J. K.; Lawrence, R. M.; Lawson, J. E.; Holava, H. M.; Partyka, R. A. Eur. Pat. Appl. EP 94-113800, 1994.
11. More concentrated ammonia solutions (2 N in MeOH) were used with the larger scale reactions which require SPE columns with larger amounts of sorbent (≥ 1.5 g).
12. The SPE columns utilized for these procedures were obtained from Varian Sample Preparation Products, 24201 Frampton Ave, Harbor City, California, 1-800-421-2825. The columns are functionalized silica gel matrices which allow for immediate solvent changes, even between organic and aqueous solutions, with no problems due to swelling.
13. A propylsulfonic acid SPE sorbent (PRS) was also investigated and found to efficiently retain the basic amidopiperidine products. However, the product elution was found to vary dramatically with the nature of the acid component of the newly formed amide bond. This structure dependent variable elution was not seen with the SCX sorbent presumably due to the additional hydrophobic interactions imparted by the more lipophilic ethylbenzene linker.
14. For larger quantities, the same reaction can be run in several tubes and the product combined after purification.
15. Excess amine was required to insure complete consumption of the neutral starting ester.
16. The anion exchange column, purchased in the chloride form, was converted to the hydroxide form by pre-washing with a methanolic KOH solution on the SPE workstation. Increasing the basicity of the column increased the efficiency of the removal of the p-nitrophenol.
17. EDAC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and DMAP = 4-dimethylaminopyridine.
18. For each mmol of product in the p-nitrophenyl ester approach 1.5 mmol (1 mmol, p-nitrophenol and 0.5 mmol of excess amine) of charged species must be removed. In the carbodiimide approach 3.5 mmol of charged species (1.5 mmol urea by-product, 1.5 mmol DMAP and 0.5 mmol of excess amine or acid) must be removed. Therefore, for a given amount of SPE sorbent a smaller amount of product in the carbodiimide approach can be formed in order to allow sufficient capacity to remove all impurities.
19. Unpublished results.
20. For alternative methods of solution phase synthesis of amides see: Desai, M. C; Stramiello, L. M. S. Tettrahedron Lett. 1993, 34, 7685. Smith, P. W.; Lai, J. Y. Q.; Whittington, A. R.; Cox, B.; Houston, J. G.; Stylli, C. H.; Banks, M. N.; Tiller, P. R. Bioorg. Med. Chem. Lett. 1994, 4, 2821. Boger, D. L.; Tarby, C. M.; Myers, P. L.; Caporale, L. H. J. Am. Chem. Soc. 1996, 118, 2109.
21. For alternative methods of solution phase synthesis of amides see: Desai, M. C; Stramiello, L. M. S. Tettrahedron Lett. 1993, 34, 7685. Smith, P. W.; Lai, J. Y. Q.; Whittington, A. R.; Cox, B.; Houston, J. G.; Stylli, C. H.; Banks, M. N.; Tiller, P. R. Bioorg. Med. Chem. Lett. 1994, 4, 2821. Boger, D. L.; Tarby, C. M.; Myers, P. L.; Caporale, L. H. J. Am. Chem. Soc. 1996, 118, 2109.
22. For alternative methods of solution phase synthesis of amides see: Desai, M. C; Stramiello, L. M. S. Tettrahedron Lett. 1993, 34, 7685. Smith, P. W.; Lai, J. Y. Q.; Whittington, A. R.; Cox, B.; Houston, J. G.; Stylli, C. H.; Banks, M. N.; Tiller, P. R. Bioorg. Med. Chem. Lett. 1994, 4, 2821. Boger, D. L.; Tarby, C. M.; Myers, P. L.; Caporale, L. H. J. Am. Chem. Soc. 1996, 118, 2109.
23. Myznikov, Y. E.; Koldobskii, G. I.; Vasil'eva, I. N.; Ostrovskii, V. A. J. Org. Chem. USSR (Engl. Transl.) 1988, 24, 1397.
24. Zymark Corporation, Zymark Center, Hopkinton, Massachusetts 01748, 1-800-435-9500.
25. A 10 sec delay was used after loading reaction contents onto the ion exchange column to insure adequate interaction time between the sample and the sorbent.
26. The volume required for complete elution of the product was dependent on the scale of the reaction.
27. 4 (pH 5.4); Solvent B: MeCN.
28. 1H NMR, MS, HRMS and/or elemental analyses.
29. 2.
30. 3N during the course of the reaction which caused line and valve clogging during the purification process. The precipitated salt could be solubilized by the addition of MeOH. but the MeOH caused the p-nitrophenol to elute from the SAX anion exchange column with the desired product.
31. 4.