Preparation of the key intermediate in a novel synthesis of ZD9063P: The chemical component of ADEPT, a targeted cytotoxic therapy

Organic Process Research and Development

Volumn 4, Issue 4, 2000, Pages 259-263

  Martin, David M G ^a   Siedlecki, Pawel S ^a  

^a ASTRAZENECA   (United Kingdom)

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Indexed keywords

EID: 0034407850     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op000016+     Document Type: Article

References (17)

1. Lee, S. A. Personal communication.
2. The structure of the major regioisomer of the mixture was assigned by comparison of the chemical shifts in the NMR spectra of the protons adjacent to the carbonyl groups in the glutamic acid residue in the acid and salt forms of the product. Formation of the ammonium salt resulted in an upfield shift of approximately 0.2 ppm in the position of the methylene protons, thus showing them to be adjacent to a carboxylic acid group and not an ester function.
3. Jouin, P.; Castro, B.; Zeggaf, C.; Pantaloni, A.; Senet, J. P.; Lecolier, S.; Sennyey, G. Tetrahedron Lett. 1987, 28, 1665.
4. Sheehan, J. C.; Bolhofer, W. A. J. Am. Chem. Soc. 1950, 72, 2469.
5. Cristea, I.; Mager, S.; Batiu, C.; Plé, G. Rev. Roum. Chim. 1994, 39(12), 1435.
6. Huang, X.; Luo, X.; Roupioz, Y.; Keillor, J. W. J. Org. Chem. 1997, 62, 8821.
7. Ksander, G. M.; Yuan, A. M.; Diefenbacher, C. G.; Stanton, J. L. J. Med. Chem. 1985, 28, 1606.
8. The key feature of the structural assignment was a comparison of the NMR spectra with that of CBZ-glutamic acid. The chemical shift of the methine proton in the less polar compound was significantly different from the methine proton in CBZ-glutamic acid, whereas in the more polar compound the significant difference was in the methylene protons.
9. It was not possible to analyse (HPLC or NMR) the anhydride for the presence of the diastereomer to demonstrate the absence of racemisation during the 1,3-dicyclohexylcarbodiimide-mediated ring closure reaction.
10. The anhydride of menthyloxycarbonyl-(S)-glutamic acid was subjected to a similar series of reactions. Comparison with the similar products from the enantiomeric acid allowed the four possible products to be assigned unambiguously on the HPLC trace.
11. King, J. F.; du Manoir, J R. J. Am. Chem. Soc. 1975, 97, 2566.
12. Two minor by-products are observed.
13. A crystalline product was also obtained in about the same isolated yield with (R)-α-methylbenzylamine. It was noticed that the two diastereomeric salts did crystallise at significantly different rates from the same solvent mixture, but it is not known which salt would be more useful in further work on enhancing the purity of the derived ZD9063P.
14. A sample of the regioisomeric dibenzyl ester was isolated by chromatography and its structure confirmed by NMR. Removal of the benzyl ester groups gave a compound very closely related to, but clearly different from, ZD9063P by HPLC and NMR analysis.
15. AN-area normalised.
16. Analysis by chiral HPLC using a CHI-DMB column, solvent system isohexane/2-propanol/TFA (75/25/0.1), flow 1 mL/min and detection at 254 λ. The authors are grateful to Miss Fiona J Bell for this result.
17. Residual toluene and THF were detected in both spectra.