Assessment of a reductive amination route to methyl(3-nitrobenzyl)amine hydrochloride

Organic Process Research and Development

Volumn 9, Issue 6, 2005, Pages 837-842

  Connolly, Terrence J ^a,b,c   Constantinescu, Anton ^a,c   Lane, Tim S ^a,d   Matchett, Michael ^a,c   McGarry, Patrick ^a,c   Paperna, Mariya ^a,c  

^a ROCHE BIOSCIENCE   (United States)

^b Celera ^*  (United States)

^c Chemical Development   (United States)

^d Process Analytical

Author keywords

[No Author keywords available]

Indexed keywords

EID: 28944433800     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op050120x     Document Type: Article

References (32)

1. Holmes, E. L.; Ingold, C. K. J. Chem. Soc. 1925, 1800-1821.
2. v.Braun, J.; Michaelis, R.; Spanig, H. Chem. Ber. 1937, 70, 1241-1249.
3. Meindl, W. R.; Von Angerer, E.; Schoenenberger, H.; Ruckdeschel, G. J. Med. Chem. 1984, 27, 1111-1118.
4. Neidigh, K. A.; Avery, M. A.; Williamson, J. S.; Bhattacharyya, S. J. Chem. Soc., Perkin Trans. 1 1998, 2527-2532.
5. Billman, J. H.; Diesing, A. C. J. Org. Chem. 1957, 22, 1068-1070.
6. Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett. 1990, 31, 5595-5598.
7. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897-2904.
8. Compounds 6-8 were not well retained on the LC column and eluted essentially in the void. The presence of these compounds was determined by the extracted ion chromatograms at the appropriate molecular masses.
9. Larock, R. C. Comprehensive Organic Transformations; Wiley-VCH: New York, 1999; pp 823-827.
10. March, J. Advanced Organic Chemistry, 3rd ed.; Wiley-Interscience: New York, 1985; p 1103.
11. Seyden-Penne, J. In Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York, 1991; Chapter 4, pp 137-139.
12. 3-Nitrobenzyl chloride was only available with a lead time of 12-16 weeks and a cost of ca. $750-$1650/kg.
13. Mixtures of the hydrochloride salts of 1 and 3 can be separated in a rather labor-intensive procedure that involves dissolving the mixture in water and extracting the dimer hydrochloride salt into methylene chloride. The aqueous solution containing 1 is adjusted to pH 10 and extracted with methylene chloride, and the solvent is exchanged with 2-propanol or ethanol. Dry HCl is added to precipitate the salt, and heptane is added as an antisolvent. Hydrochloride salt of 1 is then filtered and dried.
14. The condensation is also successful under biphasic conditions using methylamine hydrochloride, sodium hydroxide, and water. A higher charge of water is used in this case to ensure the sodium chloride is extracted into the aqueous layer and does not interfere with the isolation of the imine. These conditions have not been demonstrated on scales larger than 5 g.
15. Brown, H. C.; Subba Rao, B. C. J. Am. Chem. Soc. 1960, 82, 681-686.
16. Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky, T. P. J. Org. Chem. 1973, 38, 2786-2792.
17. Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz, M. J. Org. Chem. 1999, 64, 6263-6274.
18. Hutchins, R. O.; Learn, K.; Nazer, B.; Pytlewski, D.; Pelter, A. Org. Prep. Proced. Int. 1984, 16, 335-372.
19. Lane, C. F. Aldrichimica Acta 1973, 6, 51-58.
20. Couturier, M.; Andresen, B. M.; Tucker, J. L.; Dube, P.; Brenek, S. J.; Negri, J. T. Tetrahedron Lett. 2001, 42, 2763-2766.
21. Couturier, M.; Tucker, J. L.; Andresen, B. M.; Dube, P.; Brenek, S. J.; Negri, J. T. Tetrahedron Lett. 2001, 42, 2285-2288.
22. Couturier, M.; Tucker, J. L.; Andresen, B. M.; Dube, P.; Negri, J. T. Org. Lett. 2001, 3, 465-467.
23. Andrews, G. C.; Crawford, T. C. Tetrahedron Lett. 1990, 21, 693-696.
24. Billman, J. H.; McDowell, J. W. J. Org. Chem. 1961, 26, 1437-1440.
25. Pelter, A.; Rosser, R. M.; Mills, S. J. Chem. Soc., Perkin Trans. 1 1984, 717-720.
26. The use of gaseous hydrogen chloride in the Palo Alto Pilot Plant facility is complicated by the Santa Clara Toxic Gas Ordinance (Ordinance No. NS-517.44, Code of Santa Clara, Division B11, Chapter X).
27. Although glass lined reactors would be used during the scale-up of this chemistry, contact with stainless steel could occur, particularly during transfers between reactors where stainless steel fittings are commonly used. We have not explored the impact of vessel contamination with metal catalysts such as Ni and Pd, but based on the work by Couturier, this situation should be avoided, since arylnitro reduction is quite facile and exothermic in protic solvents. See refs 20-22.
28. It is important to minimize the amount of water carried forward. The methylene chloride solution of imine 5 had 0.02% water (KF method) prior to adding methanesulfonic acid. See ref 29.
29. Other bases were explored as acid scavengers in the imine forming stage. Triethylamine partitioned in the organic layer and consistently led to dimer formation during the reduction. Incomplete imine formation was observed when N-methylmorpholine was used as the base.
30. See the information provided for nitrobenzaldehydes, nitrobenzyl compounds, and nitro compounds in Bretherick's Handbook of Reactive Chemical Hazards, 5th edition, P. G. Urben (editor) Butterworth-Heinemann, Boston 1995.
31. On this scale, the addition required 20 min. A cooling bath was not used.
32. On a large scale, this quench was done in a vessel that was connected to a system that diluted the off-gas with nitrogen.