A new industrial process for oxcarbazepine

Organic Process Research and Development

Volumn 9, Issue 3, 2005, Pages 272-277

  Fuenfschilling, Peter C ^a   Zaugg, Werner ^a   Beutler, Ulrich ^a   Kaufmann, Daniel ^a   Lohse, Olivier ^a   Mutz, Jean Paul ^a   Onken, Ulrich ^a   Reber, Jean Louis ^a   Shenton, David ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICONVULSIVE AGENT; OXCARBAZEPINE;

ARTICLE; DRUG SYNTHESIS; FRIEDEL CRAFTS REACTION; HALOGENATION; OXIDATION; RING CLOSING METATHESIS;

EID: 20444459136     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op049760a     Document Type: Article

References (31)

1. 2) to 2,2′-diaminodibenzyl. Step 3: ring-closure reaction with PPA at 330°C to iminodibenzyl 4a. Step 4: catalytic dehydrogenation (FeOx/550°C) to 2.
2. 2: Ishii, Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. J. Org. Chem. 1996, 61, 4520.
3. 3/t-BuOOH: Muzart, J. Tetrahedron Lett. 1987, 28, 2131.
4. 2/t-BuOOH: Feldberg, L.; Sasson, Y. Tetrahedron Lett. 1996, 37, 2063. None of these reactions proved to be as clean as it is required for the development of an industrial process. This work was carried out by B. Pugin at Solvias.
5. Haász, F.; Galamb, V. Synth. Commun. 1994, 24, 683.
6. Milanese, A. WO 9621649, 1996.
7. Lohse, O.; Beutler, U.; Fünfschilling, P.; Furet, P.; France, J.; Kaufmann, D.; Penn, G.; Zaugg, W. Tetrahedron Lett. 2001, 42, 385.
8. Kaufmann, D.; Fünfschilling, P.; Beutler, U.; Hoehn, P.; Lohse, O.; Zaugg, W. Tetrahedron Lett. 2004, 45, 5275.
9. Since its introduction into production, several hundred tons of oxcarbazepine have been manufactured with this new process.
10. Crestini, C.; Saladino, R. Synth. Commun. 1994, 24, 2835.
11. Tamura, Y.; Uenishi, J.; Maeda, H.; Choi, H.-D.; Ishibashi, H. Synthesis 1981, 534. For our investigation compound 10 was purchased from Amoli Organic Ltd., 407 Dalamal House, J. B. Road, Nariman Point, Mumbai-21, India.
12. Mass ratio upper phase/lower phase = 60:1.
13. If the water formed during the reaction is removed by evaporation under reduced pressure, the conversion to 11 comes to a complete standstill. The equilibrium between 10 and 14 is also supported from literature data indicating the relatively easy deprotonation of benzolactams: Kresge, A. J.; Meng, Q. Can. J. Chem. 1999, 77, 1528.
14. a of the open-chain analogue N-phenyl-N-methyl phenylacetamide: 24.6.
15. The nature of this precipitate has not been investigated.
16. Reaction enthalpy of the lithiation step: -226 kJ/mol. To get an optimal yield, the addition of butyllithium should be performed in 2 h or less.
17. Reaction enthalpy of the acylation with dimethyl carbonate is -21 kJ/mol and with methyl chloroformate is -185 kJ/mol. To get an optimal yield, the addition of dimethyl carbonate and methyl chloroformate should not exceed 2 h.
18. A 1:1 mixture of the dianion 12 and the alkali salt of 5 slowly decomposes at -10°C; however, the mixture is stable at -40°C over several hours.
19. Since the deprotonation of monoanion 11 is very fast, lithiation to 12 can also be performed at -40°C. Acylation with dimethyl carbonate at -40 °C is too slow for a production process.
20. Volumes are 50 mL each. Alternatively, a cooled reactor tube was used but proved to be unsuitable due to insufficient mixing.
21. Water traces in the solution of 11 were compensated by an equivalent increase of the butyllithium feed.
22. 3 continuous reactors was found to be technically feasible but has not been implemented because existing batch reactor equipment was available.
23. 5/methane sulfonic acid [Eaton, P. E.; Carlsen, G. R.; Lee, J. T. J. Org. Chem, 1973, 38, 4071] led not to 6 but gave 10-methansulfonyloxy-N-methoxycarbonyliminostilbene in moderate yield. On the other hand, Friedel-Crafts acylation via the acid chloride of 5 with aluminium chloride in a chlorinated solvent proved to be a feasible alternative to PPA for the conversion of 5 to 6.
24. R = -180 kJ/mol.
25. Drying of the wet filter cake would not only decrease productivity but would also have a negative impact on the stability of 7. Traces of acid catalyze the hydrolysis of 7 to the keto-compound 6. It was found that the dry compound 7 is very sensitive to moisture, whereas the methanol damp product is stable. No such problems are encountered in the drying process of 8 due to the alkaline reaction and working-up conditions applied.
26. Initially, trimethyl orthoformate was used to complete the enol ether formation according to literature methods. Later it was found that a complete reaction is also obtained with methanol alone; apparently the precipitation of 7 is sufficient for shifting the reaction equilibrium completely to the product side.
27. The alkaline hydrolysis of 6 to 15 is feasible, but somewhat less clean than the hydrolysis of 7.
28. Under comparable reaction conditions, the carbamoylation of 8 is ca. 500 times faster than that of 2.
29. Addition of small amounts of 2-methoxypropene, which eagerly consumes water under the applied reaction condition, helps to suppress the hydrolysis to 15.
30. Carbamoylation of 15 to 1 could be achieved only by using chlorosulfonyl isocyanate. No reaction occurs with isocyanic acid at 50°C, and no 10,11-dihydro-10-chloro-5H-dibenz[b,f]azepine-5-carbonyl chloride is formed if phosgene is added to 15.
31. Washing with water is performed to eliminate sodium chloride and acetamide; the latter is formed in a parallel reaction of acetic acid with isocyanic acid, T. Takahashi et al. Japan Patent, JP 48020522, 1973. Washing with acetone is performed to eliminate a drying step. The major part of water has to be reduced from the wet filter cake to keep the amount of formic acid small for dissolving the material in the final purification step.