Asymmetric catalytic reduction of oxcarbazepine

• US 9,206,135 B2
• Filed: 10/15/2012
• Issued: 12/08/2015
• Est. Priority Date: 07/29/2005
• Status: Active Grant

• Current Assignee: BIAL Portela & Ca, SA
• Original Assignee: BIAL Portela & Ca, SA
• Inventors: Learmonth, David Alexander, Grasa, Gabriela Alexandra, Zanotti-Gerosa, Antonio
• Primary Examiner(s): Coleman, Brenda
• Application Number:
  US13/651,844
• Publication Number:
  US 20130041146A1
• Time in Patent Office: 1,149 Days
• Field of Search: 540/589, 514/217
• US Class Current: 1/1
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: C07D 223/22 Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
• CPC Class Codes: C07D 223/28 having a single bond between positions 10 and 11

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 C_1-6 alkoxy and C_1-6 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 C_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.

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);

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);

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);

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.