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Synthesis 2006(16): 2659-2664  
DOI: 10.1055/s-2006-942487
PAPER
© Georg Thieme Verlag Stuttgart · New York

Use of Silyl Ester and Enamine Protection for an Efficient Alternate Synthesis of (1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY544344·HCl)

Jared W. Fennell*, Michael J. Semo, David D. Wirth, Radhe K. Vaid
Chemical Product Research and Development, Tippecanoe Laboratories, Eli Lilly and Company, Lafayette, IN 47902, USA
Fax: +1(317)2764507; e-Mail: Fennell_Jared_W@Lilly.com;
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Publication History

Received 28 February 2006
Publication Date:
12 July 2006 (online)

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Abstract

An alternate synthesis of title compound (5) using N-(2-methoxycarbonyl-1-methylvinyl)-l-alanine sodium salt (6) and 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1) was successfully completed. Incorporation of silyl ester protection and the use of an enamine-protecting group allowed for the elimination of several processing steps.

Keywords

acylations - protecting groups - amino acids - drugs - process development

    References

  • 1Preparation of prodrugs of exitatory amino acids:
  • 1 Bueno Melendo A, Coffey DS, Dantzig AH, De Dios A, Dominguez-Fernandez C, Herin M, Hillgren KM, Martin JA, Martin-Carbejas LM, Martinez-Grau MA, Massey SM, Moher RD, Monn JA, Montero Sagado C, Pedersen SW, Pedregal-Tercero C, Sweetana SA, and Valli MJ. inventors; PCT Int. Appl., WO  2002055481 A1.  ; Chem. Abstr. 2002, 137, 94004
    Google Scholar
  • 2a Helton DR, Kallman MJ, Monn JA, Schoepp DD, and Tizzao JP. inventors; US Patent,  5661184.  ; Chem. Abstr. 1997, 127, 205300
    Crossref
  • 2b Monn JA. Valli MJ. Massey SM. Wright RA. Salhoff CR. Jonson BG. Howe T. Alt CA. Rhodes GA. Robey RL. Griffey KR. Tizzano JP. Kallman MJ. Helton DR. Schoepp DD. J. Med. Chem.  1997,  40:  528 
    CrossrefGoogle Scholar
  • 2c Monn JA. Valli MJ. Massey SM. Hansen MM. Kress TJ. Wepsiec JP. Harkness AR. Grutsch JL. Wright RA. Johnson BG. Andis SL. Kingston A. Tomlinson R. Lewis R. Griffey KR. Tizzano JP. Schoepp DD. J. Med. Chem.  1999,  42:  1027 
    CrossrefGoogle Scholar
  • 2d Schoepp DD. Jonson BG. Wright RA. Salhoff CR. Mayne NG. Wu S. Cockerham SL. Burnett JP. Belagaje R. Bleakman D. Monn JA. Neuropharmacology  1997,  36:  1 
    CrossrefGoogle Scholar
  • 3a Dane E. Dockner T. Chem. Ber.  1965,  789 
    Google Scholar
  • 3b Dane E. Dockner T. Angew. Chem., Int. Ed. Engl.  1964,  3:  439 
    Google Scholar
  • 3c Kocienski PJ. Protecting Groups   Georg Thieme Verlag; Stuttgart, New York: 1994.  p.230-233  
    Google Scholar
  • 3d Green TW. Wuts PGM. Protection for the Amino Group, In Protecting Groups in Organic Synthesis   2nd ed.:  Wiley; New York: 1991.  Chap 7.
    Google Scholar
  • 3e Barton JW. In Protective Groups in Organic Chemistry   McOmie JFW. Plenum Press; New York: 1973.  p.67 
    Google Scholar
  • 4 Dane E. Drees F. Konrad P. Dockner T. Angew. Chem., Int. Ed. Engl.  1962,  1:  658 
    Google Scholar
  • 6 Coffey DS. Hawk MKN. Pedersen SW. Ghera SJ. Marler PG. Dodson PN. Lytle ML. Org. Process Res. Dev.  2004,  8:  945 
    CrossrefGoogle Scholar
  • 7 Bryant BP. Leftheris K. Quinn JV. Brand JG. Amino Acids  1993,  4:  73 
    CrossrefGoogle Scholar
5

KF analysis was used to determine quantity of water to add to obtain a 10% by weight solution of water prior to addition to anti-solvent.