Rapid, continuous solution-phase peptide synthesis: Application to peptides of pharmaceutical interest

Organic Process Research and Development

Volumn 7, Issue 1, 2003, Pages 28-37

  Carpino, Louis A ^a   Ghassemi, Shahnaz ^a   Ionescu, Dumitru ^a   Ismail, Mohamed ^a   Sadat Aalaee, Dean ^a,b   Truran, George A ^a   Mansour, E M E ^a   Siwruk, Gary A ^b   Eynon, John S ^b   Morgan, Barry ^b,c  

^a UNIVERSITY OF MASSACHUSETTS   (United States)

^b Biomeasure Inc   (United States)

^c Praecis Pharmaceuticals Incorporated   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSERYLASPARTYLLYSYLPROLYLPROLINE HYDROXIDE; AMINE; CARBONYL DERIVATIVE; GROWTH HORMONE RELEASING FACTOR DERIVATIVE; GROWTH HORMONE RELEASING FACTOR[21-29]; OCTAPEPTIDE; PARATHYROID HORMONE DERIVATIVE; PARATHYROID HORMONE[1-12]; PARATHYROID HORMONE[13-34]; PARATHYROID HORMONE[23-34]; SILICA GEL; TRIS(2 AMINOETHYL)AMINE; UNCLASSIFIED DRUG;

ARTICLE; DEPROTECTION REACTION; DRUG PURITY; DRUG SYNTHESIS; FILTRATION; HORMONE SYNTHESIS; METHODOLOGY; PEPTIDE SYNTHESIS; SCALE UP; SOLID;

EID: 0037286669     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0202179     Document Type: Article

References (28)

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4. Structure 1 represents a mixture of the two adducts obtained by addition of 4-AMP to DBF through either the secondary or primary amino functions. See footnote 9 of ref 1b.
5. For general methods of on-resin monitoring of solid-phase syntheses see: Lloyd-Williams, P.; Albericio, F.; Giralt, E. Chemical Approaches to the Synthesis of Peptides and Proteins; CRC Press: Boca Raton, FL, 1997; p 67.
6. Moor, W. T. Solid-Phase Peptide Synthesis. In Methods in Enzymology; Fields, G. B., Ed.; Academic Press: San Diego, CA, 1997; Vol. 289, p 520.
7. Siwruk, G. A.; Eynon, J. S. Liquid-Phase Synthesis of Peptides and Peptide Derivatives. U.S. Patent 5,516,891, 1996.
8. Dietrich, J. B.; Hildebrand, P.; Jeker, L. B.; Pansky, A.; Eberle, A. N.; Begliner, C. Regul. Pept. 1994, 53, 165.
9. Unpublished results, Biomeasure, Inc.
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11. No attempts were made to optimize the solid-phase synthesis. The conditions chosen were based on those used for other related syntheses carried out in our laboratory. Any number of other resins or solvent/coupling reagent combinations may well give better results than those described here. It is not our intention to compare the purities of the solution and solid-phase products, bur merely to note that the solution method provides a product of acceptable purity.
12. (a) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H.-G.; DeSelms, R. H. J. Am. Chem. Soc. 1990, 112, 9651.
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15. (b) Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201. All uronium/guanidinium salts used in the present work were the guanidinium isomers (N-HBTU, N-HATU, N-HAPyU). For a discussion of the two forms and methods for the synthesis of the corresponding O-isomers see: Carpino, L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F.; Zhang, C.; Lee, Y.; Foxman, F. M.; Henklein, P.; Hanay, C.; Mügge, C.; Wenschuh, H.; Klose, J.; Beyermann, M.; Bienert, M. Angew. Chem., Int. Ed. 2002, 41, 441.
16. (b) Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201. All uronium/guanidinium salts used in the present work were the guanidinium isomers (N-HBTU, N-HATU, N-HAPyU). For a discussion of the two forms and methods for the synthesis of the corresponding O-isomers see: Carpino, L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F.; Zhang, C.; Lee, Y.; Foxman, F. M.; Henklein, P.; Hanay, C.; Mügge, C.; Wenschuh, H.; Klose, J.; Beyermann, M.; Bienert, M. Angew. Chem., Int. Ed. 2002, 41, 441.
17. Carpino, L. A.; Chao, H.-G.; Ghassemi, S.; Mansour, E. M. E.; Riemer, C.; Warrass, R.; Sadat-Aalaee, D.; Truran, G. A.; Imazumi, H.; El-Faham, A.; Ionescu, D.; Ismail, M.; Kowalski, T. L.; Han, C.-H.; Wenschuh, H.; Beyermann, M.; Bienert, M.; Shroff, H.; Albericio, F.; Triolo, S.; Sole, N. A.; Kates, S. A. J. Org. Chem. 1995, 60, 7718.
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19. Rapp Polymere, GmbH, Ernst-Simon Str., 9, D-72072 Tübingen, Germany.
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21. (a) Carpino, L. A.; Philbin, M.; Ismail, M.; Truran, G. A.; Mansour, E. M. E.; Iguchi, S.; Ionescu, D.; El-Faham, A.; Riemer, C.; Warrass, R.; Weiss, M. R.; J. Am. Chem. Soc. 1997, 119, 9915.
22. (b) Carpino, L. A.; Ismail, M.; Truran, G. A.; Mansour, E. M. E.; Iguchi, S.; Ionescu, D.; El-Faham, A.; Riemer, C.; Warrass, R. J. Org. Chem. 1999, 64, 4324.
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24. Any amino acid which carries a hydrophobic group as part of the R-group of species 8 should be subject to this difficulty. The Asn analogue can be handled similarly.
25. 2 at 0°C in DCM for 30 min the percent of lactam and amide, respectively, were as follows: coupling system lactam amide N-HATU/HOBt/DIEA - 97.1 N-HATU/HOBt/TMP 32.9 65.1 N-HBTU/HOBt/DIEA - 96.2 N-HBTU/HOBt/TMP 54.7 33.1 TFFH/DIEA 99.0 - DCC/DMAP 47.0 28.8 Generally when stand-alone coupling reagents derived from HOBt or HOAt are used in the presence of the latter as additive, the choice of additive parallels thai built into the coupling reagent. For other cases in which mixed systems are reported, see: (a) Lescrinier, T.; Hendrix, C.; Kerremans, L.; Rozenski, J.; Link, A.; Samyu, B.; Van Aerschot, A.; Lescrinier, E.; Eritja, R.; Van Beeumen, J.; Herdewijn, P. Chem. Eur. J. 1998, 4, 425. (b) Zhang, Z.; Van Aerschot, A.; Chaltin, P.; Busson, R.; Herdewijn, P. Collect. Czech. Chem. Commun. 2001, 66, 923. (c) Suter, G.; Stoykova, S. A.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2000, 83, 2961. (d) Tselios, T.; Daliani, I.; Probert, L.; Deraos, S.; Matsoukas, E.; Roy, S.; Pires, J.; Moore, G.; Matsoukas, J. Bioorg. Med. Chem. 2000, 8, 1903.
26. 2 at 0°C in DCM for 30 min the percent of lactam and amide, respectively, were as follows: coupling system lactam amide N-HATU/HOBt/DIEA - 97.1 N-HATU/HOBt/TMP 32.9 65.1 N-HBTU/HOBt/DIEA - 96.2 N-HBTU/HOBt/TMP 54.7 33.1 TFFH/DIEA 99.0 - DCC/DMAP 47.0 28.8 Generally when stand-alone coupling reagents derived from HOBt or HOAt are used in the presence of the latter as additive, the choice of additive parallels thai built into the coupling reagent. For other cases in which mixed systems are reported, see: (a) Lescrinier, T.; Hendrix, C.; Kerremans, L.; Rozenski, J.; Link, A.; Samyu, B.; Van Aerschot, A.; Lescrinier, E.; Eritja, R.; Van Beeumen, J.; Herdewijn, P. Chem. Eur. J. 1998, 4, 425. (b) Zhang, Z.; Van Aerschot, A.; Chaltin, P.; Busson, R.; Herdewijn, P. Collect. Czech. Chem. Commun. 2001, 66, 923. (c) Suter, G.; Stoykova, S. A.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2000, 83, 2961. (d) Tselios, T.; Daliani, I.; Probert, L.; Deraos, S.; Matsoukas, E.; Roy, S.; Pires, J.; Moore, G.; Matsoukas, J. Bioorg. Med. Chem. 2000, 8, 1903.
27. 2 at 0°C in DCM for 30 min the percent of lactam and amide, respectively, were as follows: coupling system lactam amide N-HATU/HOBt/DIEA - 97.1 N-HATU/HOBt/TMP 32.9 65.1 N-HBTU/HOBt/DIEA - 96.2 N-HBTU/HOBt/TMP 54.7 33.1 TFFH/DIEA 99.0 - DCC/DMAP 47.0 28.8 Generally when stand-alone coupling reagents derived from HOBt or HOAt are used in the presence of the latter as additive, the choice of additive parallels thai built into the coupling reagent. For other cases in which mixed systems are reported, see: (a) Lescrinier, T.; Hendrix, C.; Kerremans, L.; Rozenski, J.; Link, A.; Samyu, B.; Van Aerschot, A.; Lescrinier, E.; Eritja, R.; Van Beeumen, J.; Herdewijn, P. Chem. Eur. J. 1998, 4, 425. (b) Zhang, Z.; Van Aerschot, A.; Chaltin, P.; Busson, R.; Herdewijn, P. Collect. Czech. Chem. Commun. 2001, 66, 923. (c) Suter, G.; Stoykova, S. A.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2000, 83, 2961. (d) Tselios, T.; Daliani, I.; Probert, L.; Deraos, S.; Matsoukas, E.; Roy, S.; Pires, J.; Moore, G.; Matsoukas, J. Bioorg. Med. Chem. 2000, 8, 1903.
28. 2 at 0°C in DCM for 30 min the percent of lactam and amide, respectively, were as follows: coupling system lactam amide N-HATU/HOBt/DIEA - 97.1 N-HATU/HOBt/TMP 32.9 65.1 N-HBTU/HOBt/DIEA - 96.2 N-HBTU/HOBt/TMP 54.7 33.1 TFFH/DIEA 99.0 - DCC/DMAP 47.0 28.8 Generally when stand-alone coupling reagents derived from HOBt or HOAt are used in the presence of the latter as additive, the choice of additive parallels thai built into the coupling reagent. For other cases in which mixed systems are reported, see: (a) Lescrinier, T.; Hendrix, C.; Kerremans, L.; Rozenski, J.; Link, A.; Samyu, B.; Van Aerschot, A.; Lescrinier, E.; Eritja, R.; Van Beeumen, J.; Herdewijn, P. Chem. Eur. J. 1998, 4, 425. (b) Zhang, Z.; Van Aerschot, A.; Chaltin, P.; Busson, R.; Herdewijn, P. Collect. Czech. Chem. Commun. 2001, 66, 923. (c) Suter, G.; Stoykova, S. A.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2000, 83, 2961. (d) Tselios, T.; Daliani, I.; Probert, L.; Deraos, S.; Matsoukas, E.; Roy, S.; Pires, J.; Moore, G.; Matsoukas, J. Bioorg. Med. Chem. 2000, 8, 1903.