Efficient and scalable method for the selective alkylation and acylation of secondary amines in the presence of primary amines

Organic Process Research and Development

Volumn 9, Issue 1, 2005, Pages 102-104

  Laduron, Frédéric ^a   Tamborowski, Vanessa ^a   Moens, Luc ^a   Horváth, András ^a   De Smaele, Dirk ^a   Leurs, Stef ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE;

ACYLATION; ALKYLATION; ARTICLE; CHEMICAL REACTION; DEPROTECTION REACTION; HYDROLYSIS KINETICS; PHASE SEPARATION; REACTION ANALYSIS; SCALE UP; SEPARATION TECHNIQUE; SUBSTITUTION REACTION;

EID: 13844298881     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op049812w     Document Type: Article

References (13)

1. (a) Theodoridis, G. Tetrahedron 2000, 56, 2339.
2. (b) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999.
3. O'Sullivan, M. C.; Dalrymple, D. M. Tetrahedron Lett. 1995, 36, 3451
4. (a) Krakowiak, K. E.; Bradshaw, J. S. Synth. Commun. 1998, 28, 3451.
5. (b) Xu, D.; Mattner, P. G.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 1996, 37, 5301.
6. Prugh, J. D.; Birchenough, L. A.; Eghertson, M. S. Synth. Commun. 1992, 22, 2357.
7. (a) Pedrosa, R.; Andrés, C.; Duque-Soladana, J. P.; Rosón, C. D. Tetrahedron: Asymmetry 2000, 11, 2809.
8. (b) Fülöp, F.; Lázár, L.; Pelczer, I.; Bernáth, G. Tetrahedron 1988, 44, 2993.
9. 3): 28.31, 29.63, 39.27, 43.68, 47.68, 79.09, 154.71. Method C for Boc protection: MIBK (2 L/M) was added to a flask containing the diamine hydrochloride salt (1 equiv) and sodium carbonate (2.5 equiv). The heterogeneous mixture was heated to reflux under nitrogen, and water was removed from the reaction mixture with a Dean-Stark trap. When the imine formation went to completion, the flask was cooled to 0°C. Boc anhydride (1 equiv) dissolved in a minimum of MIBK was then added dropwise to the flask. After stirring for 0.5 h at room temperature, water (0.5 L/M) was added. The aqueous layer was split off, and MIBK was evaporated under reduced pressure leading to the imine intermediate. Water and 2-propanol were then added, and the mixture was heated to 50°C until completion of the hydrolysis. Solvents were then distilled off providing the free primary amine. Method C for alkylation: MIBK (2 L/M) was added to a flask containing the diamine hydrochloride salt (1 equiv) and sodium carbonate (3.5 equiv). The heterogeneous mixture was heated to reflux under nitrogen, and water was removed from the reaction mixture with a Dean-Stark trap. When the imine formation went to completion, the flask was cooled to room temperature. Alkyl halide (1 equiv) was then added to the mixture. After the mixture stirred overnight at room temperature, water (0.5 L/M) was added. The aqueous layer was split off, and MIBK was evaporated under reduced pressure leading to the imine intermediate. Water and 2-propanol were then added, and the mixture was heated to 50°C until completion of the hydrolysis. Solvents were then distilled off providing the free primary amine.
10. 3): 1.14-1.27 (m, 1 H), 1.27-1.39 (m, 1 H), 1.55 (ddd, J = 12.7, 6.1, 2.7 Hz, 1 H), 1.72-1.83 (m, 3 H), 1.92 (td, J = 11.5, 2.5 Hz, 1 H), 2.35-2.50 (m, 2 H), 2.69 (dd, J = 12.2, 10.0 Hz, 1 H), 2.81-2.89 (m, 1 H), 3.02 (t, J = 3.6 Hz, 1 H), 3.03-3.08 (m, 1 H), 3.32 (s, 3 H), 3.38 (br, 3H), 3.41 (t, J = 6.4 Hz, 2 H), 3.63 (td, J = 9.5, 4.4 Hz, 1 H). Products identified by comparison with authentical samples made by literature methods: (tert-butyl 4-(aminomethyl) piperidine-1-carboxylate) Yoneda, Y.; Kawajiri, S.; Hasegawa, A.; Kito, F.; Katano, S.; Takano, E.; Mimura, T. Bioorg. Med. Chem. Lett. 2001, 11, 1261; (tert-butyl 4-aminopiperidine-1-carboxylate) Mach, R. H.; Luedtke, R. R.; Unsworth, C. D. et al. J. Med. Chem. 1993, 36, 3707; (tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate) Yang, L.; Patchett, A. A.; Pasternak, A. et al. WO 9845285; (tert-butyl (2-aminoethyl)benzylcarbamate) Kruijtzer, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J. Tetrahedron Lett. 1997, 38 (30), 5335; (1-benzylpiperidine-4-amine) Acros no. 18766. Identity of all products was also confirmed at the level of their crystalline derivatives which are pharmaceutical intermediates under patenting.
11. 3): 1.14-1.27 (m, 1 H), 1.27-1.39 (m, 1 H), 1.55 (ddd, J = 12.7, 6.1, 2.7 Hz, 1 H), 1.72-1.83 (m, 3 H), 1.92 (td, J = 11.5, 2.5 Hz, 1 H), 2.35-2.50 (m, 2 H), 2.69 (dd, J = 12.2, 10.0 Hz, 1 H), 2.81-2.89 (m, 1 H), 3.02 (t, J = 3.6 Hz, 1 H), 3.03-3.08 (m, 1 H), 3.32 (s, 3 H), 3.38 (br, 3H), 3.41 (t, J = 6.4 Hz, 2 H), 3.63 (td, J = 9.5, 4.4 Hz, 1 H). Products identified by comparison with authentical samples made by literature methods: (tert-butyl 4-(aminomethyl) piperidine-1-carboxylate) Yoneda, Y.; Kawajiri, S.; Hasegawa, A.; Kito, F.; Katano, S.; Takano, E.; Mimura, T. Bioorg. Med. Chem. Lett. 2001, 11, 1261; (tert-butyl 4-aminopiperidine-1-carboxylate) Mach, R. H.; Luedtke, R. R.; Unsworth, C. D. et al. J. Med. Chem. 1993, 36, 3707; (tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate) Yang, L.; Patchett, A. A.; Pasternak, A. et al. WO 9845285; (tert-butyl (2-aminoethyl)benzylcarbamate) Kruijtzer, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J. Tetrahedron Lett. 1997, 38 (30), 5335; (1-benzylpiperidine-4-amine) Acros no. 18766. Identity of all products was also confirmed at the level of their crystalline derivatives which are pharmaceutical intermediates under patenting.
12. 3): 1.14-1.27 (m, 1 H), 1.27-1.39 (m, 1 H), 1.55 (ddd, J = 12.7, 6.1, 2.7 Hz, 1 H), 1.72-1.83 (m, 3 H), 1.92 (td, J = 11.5, 2.5 Hz, 1 H), 2.35-2.50 (m, 2 H), 2.69 (dd, J = 12.2, 10.0 Hz, 1 H), 2.81-2.89 (m, 1 H), 3.02 (t, J = 3.6 Hz, 1 H), 3.03-3.08 (m, 1 H), 3.32 (s, 3 H), 3.38 (br, 3H), 3.41 (t, J = 6.4 Hz, 2 H), 3.63 (td, J = 9.5, 4.4 Hz, 1 H). Products identified by comparison with authentical samples made by literature methods: (tert-butyl 4-(aminomethyl) piperidine-1-carboxylate) Yoneda, Y.; Kawajiri, S.; Hasegawa, A.; Kito, F.; Katano, S.; Takano, E.; Mimura, T. Bioorg. Med. Chem. Lett. 2001, 11, 1261; (tert-butyl 4-aminopiperidine-1-carboxylate) Mach, R. H.; Luedtke, R. R.; Unsworth, C. D. et al. J. Med. Chem. 1993, 36, 3707; (tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate) Yang, L.; Patchett, A. A.; Pasternak, A. et al. WO 9845285; (tert-butyl (2-aminoethyl)benzylcarbamate) Kruijtzer, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J. Tetrahedron Lett. 1997, 38 (30), 5335; (1-benzylpiperidine-4-amine) Acros no. 18766. Identity of all products was also confirmed at the level of their crystalline derivatives which are pharmaceutical intermediates under patenting.
13. 3): 1.14-1.27 (m, 1 H), 1.27-1.39 (m, 1 H), 1.55 (ddd, J = 12.7, 6.1, 2.7 Hz, 1 H), 1.72-1.83 (m, 3 H), 1.92 (td, J = 11.5, 2.5 Hz, 1 H), 2.35-2.50 (m, 2 H), 2.69 (dd, J = 12.2, 10.0 Hz, 1 H), 2.81-2.89 (m, 1 H), 3.02 (t, J = 3.6 Hz, 1 H), 3.03-3.08 (m, 1 H), 3.32 (s, 3 H), 3.38 (br, 3H), 3.41 (t, J = 6.4 Hz, 2 H), 3.63 (td, J = 9.5, 4.4 Hz, 1 H). Products identified by comparison with authentical samples made by literature methods: (tert-butyl 4-(aminomethyl) piperidine-1-carboxylate) Yoneda, Y.; Kawajiri, S.; Hasegawa, A.; Kito, F.; Katano, S.; Takano, E.; Mimura, T. Bioorg. Med. Chem. Lett. 2001, 11, 1261; (tert-butyl 4-aminopiperidine-1-carboxylate) Mach, R. H.; Luedtke, R. R.; Unsworth, C. D. et al. J. Med. Chem. 1993, 36, 3707; (tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate) Yang, L.; Patchett, A. A.; Pasternak, A. et al. WO 9845285; (tert-butyl (2-aminoethyl)benzylcarbamate) Kruijtzer, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J. Tetrahedron Lett. 1997, 38 (30), 5335; (1-benzylpiperidine-4-amine) Acros no. 18766. Identity of all products was also confirmed at the level of their crystalline derivatives which are pharmaceutical intermediates under patenting.