Process development of selectively benzoylated and fluorinated glycosyl donors

Organic Process Research and Development

Volumn 14, Issue 3, 2010, Pages 623-631

  Weiberth, Franz J ^a   Gill, Harpal S ^a   Jiang, Ying ^a   Lee, George E ^a   Lienard, Philippe ^a   Pemberton, Clive ^a   Powers, Matthew R ^a   Subotkowski, Witold ^a   Tomasik, Witold ^b   Vanasse, Benoit J ^a   Yu, Yong ^a  

^a SANOFI   (France)

^b Chemical Development Support   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 77952903273     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op100053k     Document Type: Article

References (53)

1. Idris, I.; Donnelly, R. Diabetes, Obes. Metab. 2009, 11, 79
2. Frick, W.; Glombik, H.; Kramer, W.; Heuer, H.; Brummerhop, H.; Plettenburg, O. U.S. Patent 2005/0014704 A1, 2005, (WO2004052902; CAN 141:38810).
3. Frick, W.; Glombik, H.; Kramer, W.; Heuer, H.; Brummerhop, H.; Plettenburg, O. U.S. Patent 2004/0259819 A1, 2004, (WO2004052903; CAN 141:38811).
4. Williams, J. M.; Richardson, A. C. Tetrahedron 1967, 23, 1369
5. Reist, E. J.; Spencer, R. R.; Calkins, D. F.; Baker, B. R.; Goodman, L. J. Org. Chem. 1965, 30, 2312
6. Rye, C. S.; Withers, S. G. J. Am. Chem. Soc. 2002, 124, 9756
7. Card, P. J. J. Org. Chem. 1983, 48, 393
8. Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999, 64, 7048 and references cited therein
9. 19F NMR spectroscopy.
10. BAST was manufactured by Air Products and Chemicals, Inc. (www.airproducts.com) and sold as Deoxo-fluor. The containers were obtained from Entegris, Inc. (www.entegris.com).
11. Independent corrosivity studies have not yet been performed. Air Products and Chemicals, Inc. has a history of successfully manufacturing BAST and performing BAST reactions in Hastelloy equipment. Accordingly, the BAST reactions and quenches (HF generated) were performed in the pilot plant in Hastelloy C276 equipment.
12. In the subsequent deacetylation step, a 4:1 mixture of α/β-anomers of 6a is obtained regardless of anomeric composition of starting 10.
13. Poor conversions (<10 A%) resulted in attempts to directly couple 10 or 11 with 2 in the presence of Lewis acids.
14. Zhang, J.; Kováč, P. J. Carbohydr. Chem. 1999, 18, 461
15. For a recent discussion on assessing and selecting synthesis routes, see: Parker, J. S.; Bower, J. F.; Murray, P. M.; Patel, B.; Talavera, P. Org. Process Res. Dev. 2008, 12, 1060
16. and references cited therein. For a review of process chemistry objectives, see: Zhang, T. Y. Chem. Rev. 2006, 106, 2583
17. Vorbrüggen, H. Synthesis 2008, 1165
18. Price ranges for bulk quantities: 6-9 €/mol for galactose and 115-155 €/mol for methyl α- D -galactose monohydrate. The primary feedstock for these substrates is cow's milk (certified for human consumption).
19. Mowery, D. F., Jr.; Ferrante, G. R. J. Am. Chem. Soc. 1954, 76, 4103
20. Dale, J. K.; Hudson, C. S. J. Am. Chem. Soc. 1930, 52, 2534
21. Pater, R. H.; Coelho, R. A.; Mowery, D. F., Jr. J. Org. Chem. 1973, 38, 3272
22. Ratios improved slightly to 4:1 at elevated temperatures (120 °C, under pressure) in attempts to adapt concepts from reports that achieved 12:1 α/β selectivity using microwave-assisted Fischer glycosylation conditions: Bornaghi, L. F.; Poulsen, S.-A. Tetrahedron Lett. 2005, 46, 3485
23. Nüchter, M.; Ondruschka, B.; Lautenschläger, W. Synth. Commun. 2001, 31, 1277
24. The β-anomer is not suitable for use in this instance because it impacts selectivity in the benzoylation step and would lead to mixtures that interfere with isolations in downstream chemistry.
25. In preliminary screens, benzoylation appeared to have more potential for selectivity than alternative acylations, such as acetylation or pivaloylation. Also, see: Lindhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, 2nd ed.; Wiley-VCH: Weinheim, 2003; p 49.
26. Generally, anomeric-OH and primary-OH are most reactive, and equatorial-OH is more reactive than axial-OH. Based on analogy with benzoylation of methyl α- d -galactopyranoside, 6-OH > 2-OH ≈ 3-OH > 4-OH. See: Haines, A. H. Relative Reactivities of Hydroxyl Groups in Carbohydrates. In Advances in Carbohydrate Chemistry and Biochemistry; Tipson, R. S.; Horton, D., Eds.; Academic Press: New York, 1976; Vol. 33, pp 11-109.
27. Reported yield after chromatography is 38%. (β-anomer not reported): Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1982, 110, 261
28. Kováč, P.; Taylor, R. B. Carbohydr. Res. 1987, 167, 153
29. Pyridine (or alternative base) in this instance also serves as acyl transfer reagent (via in situ generated benzoyl pyridinium species) and as HCl acceptor.
30. Selective acylations using acid anhydrides: Horton, D.; Lauterback, J. H. J. Org. Chem. 1969, 34, 86
31. Chen, C.-T.; Kuo, J.-H.; Pawar, V. D.; Munot, Y. S.; Weng, S.-S.; Ku, C.-H.; Liu, C.-Y. J. Org. Chem. 2005, 70, 1188
32. Tentative structural assignments. Attempts to isolate tri-Bz species for characterization were unsuccessful.
33. In addition, the steric demands of tetrabenzoylation may override anomeric effects. For acid-catalyzed anomerization, see: Pacsu, E. Chem. Ber. 1928, 61, 1508
34. Perrin, C. L.; Armstrong, K. B. J. Am. Chem. Soc. 1993, 115, 6825
35. Isbell, H. S.; Frush, H. L. J. Org. Chem. 1958, 23, 1309
36. See ref 16a.
37. 2O can be generated in situ from BzCl and water.
38. 2O in DCM in the presence of pyridine.
39. Prepared by treating 7b with perfluorobutanesulfonyl fluoride in the presence of DBU.
40. 1H NMR data: Blattner, R.; Ferrier, R. J.; Tyler, P. C. J. Chem. Soc., Perkin Trans. I 1980, 1535
41. Fluorination occurred highly selectively with inversion at C-4. None of the 4-epimer was detected in the product or the filtrate compared to an authentic sample of the epimer synthesized independently.
42. 2-PrOH provided a similar performance, but was not employed in any other step in the synthesis of 1 in the route starting from 8b. In contrast, 1-BuOH was determined to be essential in a subsequent step in downstream chemistry. Therefore, 1-BuOH was selected as the preferred solvent because it minimized the total number of solvents employed in the overall synthesis and enhanced the opportunity for solvent recovery.
43. Isolated 11 needed to have a purity =98 A% to ensure acceptable quality of downstream products.
44. Schmidt, R. R.; Michel, J.; Roos, M. Liebigs Ann. Chem. 1984, 1343
45. Zorbax Eclipse C8, 4.6 mm - 150 mm, 3.5 μ, 220 nm, 35 °C, water/ACN/TFA, 1 mL/min, gradient program: 40/60/0.1 for 2 min, linear ramp over 13 min to 10/90/0.1. Relative retention times: tetrabenzoylated adduct of 8a, 0.95; 7a, 1.00.
46. Zorbax Eclipse C8, 4.6 mm - 150 mm, 3.5 μ, 230 nm, 35 °C, water/ACN/TFA, 1 mL/min, gradient program: 40/60/0.1 for 8 min, linear ramp over 1 min to 30/70/0.1. Relative retention times: 7a, 0.65; 9, 1.00.
47. Zorbax Eclipse C8, 4.6 mm - 150 mm, 3.5 μ, 220 nm, 35 °C, water/ACN/TFA, 1 mL/min, gradient program: linear ramp over 11 min from 40/60/0.1 to 30/70/0.1. Relative retention times: β-10, 0.94; 10, 1.00; 9, 1.12.
48. 19F NMR:-199.26 (dd, J = 51.9, 14.1 Hz).
49. HPLC assay data (wt/wt) from lab-scale batches consistently demonstrated quantitative yield for this process.
50. Zorbax Eclipse C8, 4.6 - 150 mm, 3.5 μ, 230 nm, 35 °C, water/ACN/TFA, 1 mL/min, gradient program: linear ramp over 20 min from 50/50/0.1 to 15/85/0.1. Retention times: 6a anomers, 9.5 and 10.6 min; 10, 13.6 min.
51. Zorbax Eclipse XDB-C8, 4.6 mm - 150 mm, 3.5 μ, 230 nm, 35 °C, water/ACN/TFA, 1 mL/min, gradient program: linear ramp over 5 min from 50/50/0.1 to 45/55/0.1, then linear ramp over 15 min to 10/90/0.1. Relative retention times: 14, 0.51; 7b, 1.00; 15, 1.32.
52. Zorbax Eclipse XDB-C8, 4.6 mm - 150 mm, 3.5 μ, 230 nm, 35 °C, water/ACN/TFA, 1 mL/min, gradient program: 40/60/0.1 for 1 min, linear ramp over 16 min to 20/80/0.1. Relative retention times: 7b, 0.73; 11, 1.00.
53. Zorbax Eclipse XDB-C8, 4.6 mm - 150 mm, 3.5 μ, 230 nm, 35 °C, water/ACN/TFA, 1 mL/min, gradient program: linear ramp over 16 min from 50/50/0.1 to 20/80/0.1. Relative retention times: 6b, 1.00; 11, 1.06.