Ligandless Heck coupling between a halogenated aniline and acrylonitrile catalyzed by Pd/C: Development and optimization of an industrial-scale Heck process for the production of a pharmaceutical intermediate

Organic Process Research and Development

Volumn 12, Issue 3, 2008, Pages 530-536

  Schils, Didier ^a,b,g   Stappers, Fred ^a,b   Solberghe, Geoffrey ^a,b,h   Van Heck, Richard ^a,b   Coppens, Michelle ^a,b   Van Den Heuvel, Dirk ^a,c   Van Der Donck, Peter ^a,d   Callewaert, Tom ^a,d   Meeussen, Frank ^a,d   De Bie, Erika ^a,e   Eersels, Kristof ^a,f   Schouteden, Ellen ^a,f  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^b Chemical Process Research

^c Chemical Process Control

^d Pilot Plant ^*

^e Safety Testing Laboratory

^f Chemical Production   (Belgium)

^g Euroscreen SA   (Belgium)

^h Chemin du Foriest   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 56649117022     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op8000383     Document Type: Article

References (32)

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2. Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320.
3. Review: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-3066 and references therein.
4. (a) Review: Littke, A.; Fu, G. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
5. Review: Whitecombe N. J.; Hii, K.; Gibson, S. Tetrahedron 2001, 57, 7449-7476.
6. Review oriented towards Process Chemistry: Farina, V. Adv. Synth. Catal. 2004, 346, 1553-1582.
7. (a) Beller, M.; Zapf, A.; Mägerlein, W. Chem. Eng. Technol. 2001, 24, 575-582. (b) de Vries, J. G. Can. J. Chem. 2001, 79, 1086-1092.
8. Prashad, M. Top. Organomet. Chem. 2004, 6, 181-203.
9. (a) Janssen, P. A. J.; Lewi, P. J.; Arnold, E.; Daeyaert, F.; de Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.: Andries, K.: de Bethune, M.-P.; Pauwels, R.; Das, K.: Clark, A. D., Jr.; Frenkel, Y. V.; Hughes, S. H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.; Williams, P.; Stoffels, P. J. Med. Chem. 2005, 48, 1901-1909. (b) Medicinal Chemistry synthesis of 3, unpublished results.
10. Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.; Okamoto, T. Bull. Chem. Soc. Jpn. 1988, 61, 600.
11. (a) Homogeneous conditions adapted from: Herrmann, W,; Brossmer, C.; Ofele, K.; Reisinger, C. P.; Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844-1847.
12. Heterogeneous conditions adapted from: Köhler, K.; Heidenreich, R.; Krauter, J.; Pietsch, J. Chem. Eur. J. 2002, 8, 622-631.
13. r(E) = reaction enthalpy over the entire reaction time (In this case, initial time is dosing start).
14. For palladacycles, pincers and several heterogeneous Pd catalysts, the Heck coupling occurs at high temperature (120-160 °C). At these temperatures, they have tendency to form soluble Pd° nanoparticles which are the true catalytic species. For more detailed discussion, see de Vries, J. G. Dalton Trans. 2006, 421-429 and references therein.
15. Review see:
16. Köhler, K.; Pröckl, S.; Kleist, W. Current Org. Chem. 2006, 10. 1585-1601, Review:
17. Phan, N.; Van Der Sluys, M.; Jones, C. Adv. Synth. Catal. 2006, 348, 609-679.
18. Thathagar, M.; ten Elshof, J.; Rothenberg, G. Angew. Chem., Int. Ed. 2006, 45. 2886-2890.
19. Review Jeffery, T. Tetrahedron 1996, 52, 10113-10130.
20. -. Lithium chloride gives 50% conversion while ammonium fluoride gives less than 10% conversion. For economical reasons, we selected the tetrabutylammonium chloride salt (technical grade 95% purity).
21. First results with homogeneous system (10 mol % Pd used) afforded 8 containing 6600 ppm of residual Pd.
22. (a) Lipshutz, B.; Blomgren. P. J. Am. Chem. Soc. 1999, 121, 5819-5820.
23. Lipshutz, B.; Tasler, S.; Chrisman, W.; Spliethoff, B.; Tesche, B. J. Org. Chem. 2003, 68, 1177-1189.
24. Conlon, D.; Pipik, B.; Ferdinand, S.; LeBlond, C.; Sowa, J.; Izzo, B.; Collins, P.; Ho, G.; Williams, J.; Shi, Y.; Sun, Y. Adv. Synth. Catal. 2003, 345, 931-935.
25. Interestingly these fine particles (8 μm) were observed only when the salt formation started from an 80/20 E/Z mixture
26. If the salt formation is performed on the pure E-isomer (E > 98%). much bigger crystals are obtained (average 250 μm), as determined by Lasentec experiments. All our efforts to improve the particle size of 8 starting from the 80/20 E/Z mixture 3 were unsuccessful.
27. Rework consisted of neutralization of the hydrochloride salt to liberate the base, extraction of the free base in toluene, treatment of the toluene phase with Silica-thiol followed by a solvent switch to ethanol and salt formation (yield: 80%).
28. As mentioned before in this article, at the beginning of the project, the 4-iodo-2,6-dimethylaniline 5 was not commercially available. After one year, two suppliers were found. Until now, more than seven suppliers have been evaluated. At the time we had to select the process, the price of 5 had already decreased by more than 15 times since our first order. Since then, significant decrease occurred again, confirming our assumption made about the potential of cost decrease. The iodoaniline process (cost for production of 3) is now 25% cheaper than the bromoaniline process.
29. The starting E/Z ratio of the aniline (80/20 for 3 or 98/2 for 8) is of little importance since a thermodynamic ratio (E/Z: 85/15) is obtained in the reaction conditions of next step of the synthesis.
30. The Heck product 3 is an oily residue which solidifies on standing. For ease of handling, and as the next step of the synthesis occurred in NMP, 3 is stored in NMP. This solution is stable over the time (confirmed by suitable stability experiments).
31. 3 since September 2007).
32. Conditions adapted from Masllorens, J.; Moreno-Manas, M.; Pla-Quintana, A.; Pleixats, R.; Roglans, A. Synthesis 2002, 1903-1911.