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

doi:10.1055/s-2006-942487

PAPER

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;

Abstract

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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

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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

2a Helton DR, Kallman MJ, Monn JA, Schoepp DD, and Tizzao JP. inventors; US Patent, 5661184. ; Chem. Abstr. 1997, 127, 205300

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

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

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

3a Dane E. Dockner T. Chem. Ber. 1965, 789

3b Dane E. Dockner T. Angew. Chem., Int. Ed. Engl. 1964, 3: 439

3c Kocienski PJ. Protecting Groups Georg Thieme Verlag; Stuttgart, New York: 1994. p.230-233

3d Green TW. Wuts PGM. Protection for the Amino Group, In Protecting Groups in Organic Synthesis 2nd ed.: Wiley; New York: 1991. Chap 7.

3e Barton JW. In Protective Groups in Organic Chemistry McOmie JFW. Plenum Press; New York: 1973. p.67

4 Dane E. Drees F. Konrad P. Dockner T. Angew. Chem., Int. Ed. Engl. 1962, 1: 658

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.

6 Coffey DS. Hawk MKN. Pedersen SW. Ghera SJ. Marler PG. Dodson PN. Lytle ML. Org. Process Res. Dev. 2004, 8: 945

7 Bryant BP. Leftheris K. Quinn JV. Brand JG. Amino Acids 1993, 4: 73