Claims for Patent: 9,206,135

Summary for Patent: 9,206,135

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 [RuX2(L)]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): wherein R1 is chosen from C1-6 alkoxy and C1-6 alkyl, n is a number from 0 to 5, and when n is a number from 2 to 5, R1 can be the same or different, and R2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl. The hydride source is either NR3R4R5 and formic acid, [R3R4R5NH][OOCH] and optionally formic acid, or [M][OOCH]x and formic acid, wherein R3, R4 and R5 are C1-6 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):	David Alexander Learmonth, Gabriela Alexandra Grasa, Antonio Zanotti-Gerosa
Assignee:	Bial Portela and Cia SA
Application Number:	US13/651,844
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,206,135
Patent Claims:	1. A compound being (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide and comprising about 2 ppm of ruthenium or less. 2. The compound of claim 1, having a chemical purity of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepin-5-arboxamide of about 99.96%. 3. The compound of claim 1, comprising less than 2 ppm of ruthenium. 4. The compound of claim 1, obtained by a process comprising: (i) a first step comprising reducing oxcarbazepine in the presence of a catalyst and a hydride source to obtain (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide, wherein the catalyst is prepared from a combination of [RuX2(L)]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): wherein R1 is chosen from C1-6 alkoxy and C1-6 alkyl, n is a number from 0 to 5, and when n is from 2 to 5, R1 is the same or different, and R2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl; wherein the hydride source is chosen from NR3R4R5 and formic acid, or [R3R4R5NH][OOCH], or [R3R4R5NH][OOCH] and formic acid, or [M][OOCH]x and formic acid, wherein R3, R4 and R5 are C1-6 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; and (ii) a second step wherein the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide is acylated. 5. The compound of claim 1, the (R)-isomer of (S)-(−)-10-acetoxy-10,1-dihydro-5H-dibenz/b,f/azepine-5-carboxamide being below the limit of detection. 6. The compound of claim 2, comprising less than 2 ppm of ruthenium. 7. The compound of claim 2, obtained by a process comprising: (i) a first step comprising reducing oxcarbazepine in the presence of a catalyst and a hydride source to obtain (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide, wherein the catalyst is prepared from a combination of [RuX2(L)]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): wherein R1 is chosen from C1-6 alkoxy and C1-6 alkyl, n is a number from 0 to 5, and when n is from 2 to 5, R1 is the same or different, and R2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl; wherein the hydride source is chosen from NR3R4R5 and formic acid, or [R3R4R5NH][OOCH], or [R3R4R5NH][OOCH] and formic acid, or [M][OOCH]x and formic acid, wherein R3, R4 and R5 are C1-6 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; and (ii) a second step wherein the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide is acylated. 8. The compound of claim 2, the (R)-isomer of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide being below the limit of detection. 9. The compound of claim 3, having a chemical purity of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide of about 99.96%. 10. The compound of claim 3, obtained by a process comprising: (i) a first step comprising reducing oxcarbazepine in the presence of a catalyst and a hydride source to obtain (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide, wherein the catalyst is prepared from a combination of [RuX2(L)]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): wherein R1 is chosen from C1-6 alkoxy and C1-6 alkyl, n is a number from 0 to 5, and when n is from 2 to 5, R1 is the same or different, and R2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl; wherein the hydride source is chosen from NR3R4R5 and formic acid, or [R3R4R5NH][OOCH], or [R3R4R5NH][OOCH] and formic acid, or [M][OOCH]x and formic acid, wherein R3, R4 and R5 are C1-6 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; and (ii) a second step wherein the (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide is acylated. 11. The compound of claim 3, the (R)-isomer of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide being below the limit of detection. 12. The compound of claim 4, comprising less than 2 ppm of ruthenium. 13. The compound of claim 4, having a chemical purity of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide of about 99.96%. 14. The compound of claim 4, the (R)-isomer of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide being below the limit of detection. 15. A method of treating epilepsy comprising administering the compound of claim 1 to a patient in need thereof. 16. A method of treating epilepsy comprising administering the compound of claim 3 to a patient in need thereof. 17. A method of treating epilepsy comprising administering the compound of claim 3 to a patient in need thereof. 18. A method of treating epilepsy comprising administering the compound of claim 4 to a patient in need thereof.