A scalable asymmetric synthesis of (R)-2-amino-1-(3-pyridinyl)ethanol dihydrochloride via an oxazaborolidine catalyzed borane reduction

Organic Process Research and Development

Volumn 7, Issue 3, 2003, Pages 285-288

  Duquette, Jason ^a   Zhang, Mingbao ^a   Zhu, Lei ^a   Reeves, Raymond S ^a  

^a BAYER CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 1 (3 PYRIDINYL)ETHANOL; BORANE DERIVATIVE; DIMETHYL SULFIDE; OXAZABOROLIDINE DERIVATIVE; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ADDITION REACTION; ARTICLE; ASYMMETRIC SYNTHESIS; CATALYSIS; CATALYST; ENANTIOMER; LOW TEMPERATURE; REDUCTION; STEREOCHEMISTRY;

EID: 0038384699     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0340208     Document Type: Article

References (35)

1. Chromatography was performed on borane-free chlorohydrin.
2. Bayer Co. U.S. Patent 6,051,586, April 18, 2000.
3. The enantiomerically pure chlorohydrin is also obtainable via a fermentation process. Kaneka Co. WO Patent 00/48997, August 24, 2000.
4. Singh, V. K. Synthesis 1992, 605-617.
5. Quallich, G. J.; Woodall, T. M. Tetrahedron Lett. 1993, 34, 785-788.
6. Masui, M.; Shioiri, T. Synlett 1997, 273-274.
7. Quallich used 5 mol % and Masui used 10 mol % catalyst.
8. Corey, E. J.; Shibata, S. J.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861-2863.
9. Hett, R.; Senanayake, C. H.; Wald, S. A. Tetrahedron Lett. 1998, 39, 1705-1708.
10. Hett, R.; Fang, Q. K.; Gao, Y.; Wald, S. A.; Senanayake, C. H. Org. Process Res. Dev. 1998, 2, 96-99.
11. Naylor, E. M.; Colandrea, V. J.; Candelore, M. R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Strader, C. D.; Tota, L.; Wang, P.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 1998, 8, 3087-3092.
12. Merck & Co. U.S. Patent 5,561,142, October 1, 1996.
13. (a) Hu, B.; Ellingboe, J.; Gunawan, I.; Han, S.; Largis, E.; Li, Z.; Malamas, M.; Mulvey, R.; Oliphant, A.; Sum, F.; Tillett, J.; Wong, V. Bioorg. Med. Chem. Lett. 2001, 11, 757-760.
14. (b) American Home Products Co. WO Patent 02/0623, January 24, 2002.
15. (c) The optically active bromohydrin obtained in the previous references was convened into the epoxide and opened with ammonia/methanol to yield the optically active amino alcohol. No ee was reported.
16. In the preliminary experiments, the flask containing acetic acid and the HCl cylinder were tared to determine that the desired amount was transferred into the solution. On the kilogram scale, only the cylinder tare was used. No other method was used to determine the precise molarity of the solution.
17. 6), there was 3% 3-acetylpyridine hydrochloride in the solid.
18. 1H NMR, less than 2 mol % of the product was found in the triethylamine hydrochloride solid and less than 2 mol % of triethylamine was found in the filtrate.
19. Quallich, G. J.; Woodall, T. M. Synlett 1993, 929-930.
20. 1H NMR at 2.5 ppm, which is consistent with a borane - pyridine complex.
21. Hett showed (ref 9) that the same ee was obtained in the reduction of 2-bromo-4′-(benzyloxy)-3′-nitroacetophenone when the substrate addition time was 2 h or 30 min.
22. Corey, E. J.; Bakshi; R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551-5553.
23. High ees have been obtained with oxazaborolidine catalyzed borane reductions during which borane was added into a solution of the catalyst and ketone (ref 22). These results also suggest that borane binding is fast.
24. Jones, T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar, P.; Jones, E. T. T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 763-769.
25. For the addition of ketone, excess borane is always in solution with the catalyst and intermediate 7 can form upon regeneration of 6. In this addition sequence, the borane binding rate required for a high ee is less than the rate required for a high ee under the addition of borane.
26. This low turnover frequency might be due to the stabilization of intermediate 9 via the electron withdrawing effect of the chloro substituent and the consequent delocalization of the negative charge on boron. For example, without the chloro substituent, only a 1 h addition time at 0-5°C was needed to reduce 3-acetylpyridine in 99% ee with 10 mol % of the enantiomer of catalyst 6 and with borane-dimethyl sulfide as the reducing agent (ref 6). Furthermore, it has been reported that the simultaneous addition of ketone and reducing reagent was necessary to ensure high enantioselectivity in the reduction of 2-bromo-4′-(benzyloxy)-3′-nitroacetophenone (ref 10), α-chloroacetophenone (ref 8, 31), and 2-bromo-cyclohex-2-eneone (ref 32). The only explanation provided on the need for simultaneous addition is that it "suppress[es] uncatalyzed reduction pathways" (ref 31). However, there are also examples on the reduction of 2-bromo-4′-(benzyloxy)-3′nitroacetophenone (ref 9) and α-chloroacetophenone (ref 17, 32) for which simultaneous addition was not necessary, using a different catalyst, a different butane source, or both a different catalyst and a different borane source. This may be due to the role the catalyst and borane source play in the stabilization or destabilization of intermediate 9. Another possible counterexample is that trihalomethyl ketones were reduced with excellent enantioselectivity (ref 33). However, no description of the addition mode, addition time, or time for complete conversion was provided. Also, the trihalomethyl group inverts the stereo configuration of the catalyst complex relative to the corresponding monohalomethyl ketone, which may in itself have a consequence on the rate of catalyst regeneration.
27. r = 8.57 min) was present in 2 area % based on the achiral method outlined in ref 29. The major ion detected was 224.1. Also a minor amount of 265.1 was detected.
28. 1H NMR in the final product, but its intensity was reduced by the reslurry. See the Experimental Section for more information.
29. The monohydrochloride salt is partially soluble in n-butanol and also can be isolated by filtration, albeit in lower yields.
30. It was later observed that water appears to aid the removal of some of the organic impurities. Future work might include eliminating the final azeotrope.
31. r = 7.7 min.
32. Chiralpak AD 4.6 mm x 250 mm; 1:9 (v/v) ethanol/hexane; 1.0 mL/min; isocratic 25 min; room temp; UV 254 nm.
33. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-2012.
34. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926.
35. Corey, E. J.; Link, J. O.; Bakshi, R. K. Tetrahedron Lett. 1992, 33, 7107-7110.