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Details for Patent: 8,288,532

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Details for Patent: 8,288,532

Title:Asymmetric catalytic reduction of oxcarbazepine
Abstract: A process for preparing (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide, by reduction of oxcarbazepine in the presence of a catalyst and a hydride source is disclosed. The catalyst is prepared from a combination of [RuX.sub.2(L)].sub.2 wherein X is chlorine, bromine or iodine, and L is an aryl or aryl-aliphatic ligand, with a ligand of formula (A) or formula (B): ##STR00001## wherein R.sup.1 is chosen from C.sub.1-6 alkoxy and C.sub.1-6 alkyl, n is a number from 0 to 5, and when n is a number from 2 to 5, R.sup.1 can be the same or different, and R.sup.2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl. The hydride source is either NR.sup.3R.sup.4R.sup.5 and formic acid, [R.sup.3R.sup.4R.sup.5NH][OOCH] and optionally formic acid, or [M][OOCH].sub.x and formic acid, wherein R.sup.3, R.sup.4 and R.sup.5 are C.sub.1-6 alkyl, M is an alkali metal or alkaline earth metal and x is 1 or 2. A pH from 6.5 to 8 is maintained during the process.
Inventor(s): Learmonth; David Alexander (Alfena, PT), Grasa; Gabriela Alexandra (Mantua, NJ), Zanotti-Gerosa; Antonio (Cambridge, GB)
Assignee: Bial-Portela & CA., S.A. (S. Mamede do Coronado, PT)
Filing Date:Apr 21, 2006
Application Number:11/997,104
Claims:1. A process for preparing (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide, by reduction of oxcarbazepine in the presence of a catalyst and a hydride source, wherein the catalyst is prepared from a combination of [RuX.sub.2(L)].sub.2 wherein X is chlorine, bromine or iodine, and L is an aryl or aryl-aliphatic ligand, with a ligand of formula (A) or formula (B): ##STR00010## wherein R.sup.1 is chosen from C.sub.1-6 alkoxy and C.sub.1-6 alkyl, n is a number from 0 to 5, and when n is from 2 to 5, R.sup.1 can be the same or different, and R.sup.2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl; wherein the hydride source is chosen from NR.sup.3R.sup.4R.sup.5 and formic acid, or [R.sup.3R.sup.4R.sup.5NH][OOCH] and optionally formic acid, or [M][OOCH].sub.x and formic acid, wherein R.sup.3, R.sup.4 and R.sup.5 are C.sub.1-6 alkyl, M is an alkali metal or alkaline earth metal and x is 1 or 2, and wherein during the process a pH from 6.5 to 8 is maintained.

2. The process according to claim 1, wherein X is chlorine.

3. The process according to claim 1, wherein L is p-cymene.

4. The process according to claim 1, wherein n is 1 and R.sup.1 is a methoxy group or a methyl group.

5. The process according to claim 4, wherein n is 1 and R.sup.1 is a methoxy group or a methyl group in the para position.

6. The process according to claim 1, wherein the ligand of formula (A) or formula (B) is (S,S)--N-(4-toluenesulfonyl)-di(methoxyphenyl)ethylenediamine, ((S,S)-TsDAEN), or (R,R)--N-(4-toluenesulfonyl)-di(methoxyphenyl)ethylenediamine, ((R,R)-TsDAEN).

7. The process according to claim 1, wherein the molar ratio of oxcarbazepine to the ruthenium catalyst is at least 500:1.

8. The process according to claim 7, wherein the molar ratio of oxcarbazepine to the ruthenium catalyst is at least 1500:1.

9. The process according to claim 7, wherein the molar ratio of oxcarbazepine to the ruthenium catalyst is at least 2500:1.

10. The process according to claim 1, wherein the hydride source is NR.sup.3R.sup.4R.sup.5 and formic acid.

11. The process according to claim 10, wherein less than two equivalents of NR.sup.3R.sup.4R.sup.5 and less than 1 equivalent of formic acid are added to the reaction mixture at the start of the process.

12. The process according to claim 1, wherein the hydride source is [R.sup.3R.sup.4R.sup.5NH][OOCH] and optionally formic acid.

13. The process according to claim 10, wherein less than two equivalents of [R.sup.3R.sup.4R.sup.5NH][OOCH] and less than 0.5 equivalents of formic acid are added to the reaction mixture at the start of the process.

14. The process according to claim 1, wherein the hydride source is [M][OOCH].sub.x and formic acid.

15. The process according to claim 14, wherein less than two equivalents of [M][OOCH].sub.x and less than 1 equivalent of formic acid are added to the reaction mixture at the start of the process.

16. The process according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are ethyl, propyl or butyl.

17. The process according to claim 1, wherein the pH is maintained from 6.5 to 8 by adding formic acid in a controlled manner during the course of the reaction.

18. The process according to claim 17, wherein the pH is maintained from 7.0 to 7.8 by adding formic acid in a controlled manner during the course of the reaction.

19. The process according to claim 1, wherein the reduction takes place in a solvent, wherein the solvent comprises at least one polar aprotic solvent.

20. The process according to claim 19, wherein the solvent comprises dimethylformamide or acetonitrile.

21. The process according to claim 1, wherein the hydride source comprises (i) NR.sup.3R.sup.4R.sup.5 or [M][OOCH].sub.x and (ii) formic acid; and wherein the reduction takes place in a solvent consisting of 0-25% DMF, 0-25% water and 75-95% EtOAc or 0-25% acetonitrile, 0-25% water and 75-95% EtOAc.

22. The process according to claim 12, wherein the reduction takes place in a solvent consisting of 5-25% DMF and 75-95% EtOAc, 5-25% acetonitrile and 75-95% EtOAc, 5-25% DMF and 75-95% water, or 5-25% acetonitrile and 75-95% water.

23. The process according to claim 1, wherein the process is carried out under reflux conditions.

24. The process according to claim 1, wherein the reduction takes place in the presence of a phase transfer catalyst and the phase transfer catalyst is a quaternary alkyl ammonium halide.

25. The process according to claim 1, wherein the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide is isolated either by addition of methyl tert-butyl ether (MTBE) and filtration, or by precipitation from either methanol/water or methanol/MTBE at 0-5.degree. C.

26. The process according to claim 1, wherein the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide is precipitated by removing the reaction solvent while adding water to maintain the reaction volume at a substantially constant level.

27. The process according to claim 26, wherein the precipitated (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide is isolated by filtration followed by reslurrying in ethyl acetate and filtration.

28. The process according to claim 1, wherein the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide has an optical purity in the range 92-100%.

29. The process according to claim 1, further comprising the step of acylating the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide to produce a compound of formula (C) or (D) ##STR00011## wherein R.sup.6 is hydrogen, alkyl, halogenalkyl, aralkyl, cycloalkyl, cycloalkyalkyl, alkoxy, aryl or pyridyl.

30. The process according to claim 1, further comprising the step of acylating the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide to produce (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxam- ide.

31. The process according to claim 1, further comprising the step of acylating the (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide to produce (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxam- ide.
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