Sign In to Follow Application
View All Documents & Correspondence

Process For Preparing (S) ( ) 10 Acetoxy 10, 11 Dihydro 5 H Dibenz [B,F] Azepine 5 Carboxamide And Its Esters Thereof

Abstract: Disclosed herein an enzymatic process for preparing (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (eslicarbazepine) and its esters thereof. Further, the invention provides novel intermediates of eslicarbazepine and isomers thereof, enabling high purity and yield of eslicarbazepline.

Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
12 October 2009
Publication Number
15/2011
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

MATRIX LABORATORIES LIMITED
1-1-151/1, 4TH FLOOR, SAI RAM TOWERS, ALEXANDER ROAD, SECUNDERABAD- 500 003

Inventors

1. HUSAIN, MOFAZZAL
1-1-151/1, 4TH FLOOR, SAI RAM TOWERS, ALEXANDER ROAD, SECUNDERABAD- 500 003
2. DATTA, DEBASHISH
1-1-151/1, 4TH FLOOR, SAI RAM TOWERS, ALEXANDER ROAD, SECUNDERABAD- 500 003

Specification

Field of the Invention This invention, in general relates to a process for preparing (S)-(-)-10-acetoxy-10,ll-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (eslicarbazepine) and its esters thereof. In particular, the present invention provides a novel enzymatic process for the preparation of eslicarbazepine and its esters thereof. Further, the invention provides novel intermediates of eslicarbazepine and isomers thereof, the process for preparing the same and the use of the same to prepare eslicarbazepine. Background of the Invention Eslicarbazepine acetate (ESL) [(S)-(-)-10-acetoxy-10,ll-dihydro-5H-dibenz[b,f)azepine-5-carboxamide], formerly known as BIA 2-093, is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It behaves as a voltage-gated sodium channel (VGSC) blocker and is cuTcntly under clinical development for the treatment of epilepsy and bipolar disorder. Eslicarbazepine acetate is structurally represented as shown in formula I Eslicarbazepine acetate shares with carbamazepine and oxcarbazepine, the dibenzazepine nucleus bearing the 5-carboxamide substitute, but it is structurally different at the 10 and 11-positions. This molecular variation not only results in differences in metabolism, preventing the formation of toxio epoxide metabolites such as carbamazepine-10,11 epoxide but also avoids the unnecessary production of isomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity. The synthesis and improved anticonvulsant properties of (S)-(-)-10-acetoxy-10,l 1-dihydro-5H-dibenzA3,f/azepine-5-carboxamide (BIA 2-093), and (R)-(+)-10-acetoxy-10,ll-dihydro-5H-dibenz^,f/azepine-5-carboxamide (BIA 2-059), both single-isomer drugs specifically designed to avoid such formation of racemic mixtures of active metabolites have been described in U.S. Pat. No. 5,753,646 and Benes, J. et al., J. Med. Chem., 42, 2582 2587 (1999). The key step of the synthesis of compounds BIA 2-093 and BIA 2-059 involves the resolution of racemic 10,ll-dihydro-10-hydroxy-5H-dibenz/b, f/azepine-5-carboxamide ((±)MHD) into its separate, optically pure stereoisomers, (S)-(+)-10,ll-dihydro-10-hydroxy-5H-diben2/b,f/azepine-5-cvater and saturated sodium bicarbonate solution. The organic phase was extracted and dried on sodium sulfate, evaporated the solvent under reduces pressure to give 3.3 g of colorless foam. Further, added methyl tertiary butyl ether to give solidification. The suspension was filtered and air-dried to give a white solid (3.1g; 95%). HPLC: 98% purity Example 2 Preparation of Licarbazepine ethylcarbonate 2.54 g (lOmmol) racemic licarbazepine was suspended in a mixture of 75 ml anhydrous dichloromethane and 3 ml pyricline. At ambient temperature a solution of 1.4g ethylchloroformate (13 mmol) in 5 ml anhydrous dichloromethane was added drop wise. Stirred the reaction mixture for Ihr and reaction mixture was quenched with water. The organic phase was washed with sodium hydrogen sulfate solution, water and saturated sodium bicarbonate solution. The oiganic phase was extracted and dried on sodium sulfate, evaporated the solvent under reduced pressure to give viscous oil. The viscous oil was diluted with diethyl ether to give solidification. The suspension was filtered washed with diethyl ether and dried to give 1.27g white powder (72 %). Example 3 Preparation of Licarbazepine ethyl oxalate 1.27 g (lOmmol) racemic licarbazepine was suspended in a mixture of 35 ml anhydrous dichloromethane and added 1.5 ml pyridine. At ambient temperature a solution of 1 g of freshly opened ethyl chlorooxalate in 5 ml anhydrous dichloromethane was added drop wise to the above mixture. The reaction mixture was stirred for one hour. The reaction mixture was quenched with water The organic phase was washed with dilute sodium hydrogen sulfate solution, water and saturated sodium bicarbonate solution. The organic extract was dried on sodium sulfate and evaporated under reduced pressure to give viscous oil. The viscous oil was dissolved vdth diethyl ether to give solidification. The suspension was filtered, washed with diethyl ether and dried to give desired product. Example 4 Preparation of Eslicarbazepine via enzymatic hydrolysis 6.52 g racemic licarbazepine methoxyacetate was suspended in a mixture of 30 ml 2-methyltetrahydrofuran and 75 ml 33 mM potassium phosphate buffer pH 7.3. To the mixture was added 1 ml of Protex 6L protease liquid. The tri-phasic mixture was stirred at 30 °C and pH 6.8 while the pH >vas controlled by automatic addition of 1 M sodium carbonate solution in a pH-stat set-up. The progress of reaction was monitored by HPLC and stopped the reaction after 53 % conversion [substrate 99.85 - 99.99% and 85% ee of the product alcohol]. The triphasic reaction mixture was extracted twice with dichloromethane to isolate the alcohol and ester. The organic phase was washed with saturated sodium chloride solution and dried on sodium sulfate, evaporated the solvent under reduced pressure to give 5.3 g white solid [HPLC: 99.99 % ee of (5)-ester). This material (5.3 g) was dissolved in 75 ml 2-methyl tetrahydrofuran and mixed with 53 mg (1 wt% to total) of 4-dimethyla,minopyridine, 1.5 g (15 mmol; 1.4 eq to alcohol) of succinic anhydride and 3 ml triethylamine (20 mmol; 1 eq to total). This mixture was refluxed under argon while frequently sample using achiral HPLC. The heating was continued for a total of 8h, foUowe^d by overnight cooling. A HPLC sample for the clear solution showed about 99.85 % conversion of the alcohol to hemi-succinate. The clear solution was diluted with 3 volimies of water (total volume ca 300 ml) to precipitate the desired (S)-methoxyacetate ester, A white solid was obtained, however HPLC showed still significant amounts of ester in the f.iltrate (32 % methoxyacetate and 67 % hemi-succinate). The filtrate was extracted twice with 2-MeTHF and the organic extract mixed with the earlier isolated solid. The combined solution was dried and evaporated to give 2.6 g white solid (40 % overall) of eslicarbazepine. HPLC: 99.4 % purity and 99.99 % ee of (5)-licarbazepine methoxyacetate. The water phase was acidifying with HCl (pH 3 -4) and the white solid precipitated out of (R)-enriched licarbazepine. The purified (S)-Iicarbazepine methoxy actetate was hydrolyzed using aqueous sodium hydroxide by dissolving in etha:,"iol/2-methyltetrahydrofuran to give Eslicarbazepine. HPLC: 99.6% purity and 99.99% ee. Example 5 Preparation of Eslicarbazepine acetate 2.54 g (lOmmlo) eslicarbazepine w£is suspended in 40 ml anhydrous dichloromethane and a trace amount (25 mg) of dimetliylaminopyridine (DMAP) was added. At ambient temperature a solution of 0.94 g (.2mmol) acetyl chloride in 5 ml was added drop wise, the mixture v/as stirred for 30 min, iuid then quenched the reaction mass with water and the organic phase was washed twice with dilute HCL, water and saturated sodium bicarbonate solution. The organic extract was dried on sodium sulfate, evaporated the solvent under reduced pressure to give 2,93 g (99?'o) solid of Eslicarbazepine. HPLC: 99.5% purity and 99.99 % ee. Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims. 1. A process for preparing (S)-(-)-10-acetoxy-10,ll-dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula I wherein the process comprising: a) protecting a compound of formula III Formula III with a protecting group (P< J) in the presence of a solvent to give a compound of formula IV, wherein the PG group is selected from methoxyacetyl, ethyl oxalate or ethyl carbonate; b) hydrolyzing the compound of formula IV employing an enzyme to obtain a mixture of compound of formula V and formula VI; c) treating the mixture of the compound of formula V and formula VI with an acid anhydride in the presence of a base and a solvent to obtain a mixture of compound of formula V and formula VII wherein R is HO-CO-CH2-CO-, HC)-CO-CH2-CH2-CO-, HO-CO-CH2-CH2-CH2-CO-, or the like; d) hydrolyzing the compound of formula V in presence of a base and a solvent to obtain (S)-(-)-10,ll-dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula II; e) esterifying the (S)-(-)-10,ll-dihydro-5H-dibenz[b,f]azepine-5- carboxamide of formula II to obtain the (S)-(-)-10-acetoxy-10,ll-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of formula I. 2. The process according to claim 1, wherein the protecting group is selected from methoxyacetyl, ethyl oxalate, acetate or ethylcarbonate. 3. The process according to claim 1, wherein the enzyme is selected from hydrolases. 4. The process according to claim 3, wherein the enzyme is selected from a protease. 5. The process according to claim 4, wherein the enzyme is selected from NZLlOl, NZL102, NZL103, NZL104, NZL105, NZL106, NZL107, NZL108, NZL109, NZPlOl, NZP102, NZP103, NZP104, NZP106, Protease Alcalase,Protease Savinase, Protease Everlase, Protease Neutrase, ProteaseB.amyloliquifaciens, ProteaseA.oryzae, Protease N, ProteaseA.melleus, ProteaseA.saitoi, ProteaseB.poIymyxa, Protease S.griseus, Bromelain, Papain, Ficin, Rennet (M.Miehei), Protex6L, Protex7L, Protexl3FL, ProtexML, Protexl5L, ProtexSOI,, Protex40L, Protex40XL, Protex50FP, ProtexSlFP, Protex89L, Proteinase bact, ProtexB.subtillis,Novo porcine trypsine,Novocame tender, Ac id protease, Neutral protease, Alkaline protease, Bacterial protease. Alkaline protease, protease Alcalase, protease Savinase, Protease Everlase, Protease Esperase, Bacterial protease, CalA, CalB, R M, Lipolase, LipexlOO, NZ51032, Resinase, Lecitase Ultra, Alcalase, Savinase Everlase and Esperas, Lipase A.A.niger, Lipas AKP. Fluorescens,DF cone, LipasF-AP15 R.oryzae, UpasG.P.camemberti,Lipase MM.javanicus, LipaseC.rugosa, LipaseAP6, LipaseR.arrhizus, LipaseR niveus, LipasePF, LipaseC.cylindracea, LipaseRM, LipaseHog pancreas, Lipase porcinepancreas, LipaseAlcaligenes(PL), LipaseAllcaligenes(QLM), Lipase C.cylindracea (MY), Lipase C.cylindracea (OF), Lipase B.cep:icia(SL), Lipase Ps.stutzeri(TL), Lipase wheat germ, Polarzyml2T, EST-811, EST-812, EST-813, EST-814, EST-815, EST-816, Estrase BS2, Estrase BS3, Estrase PL, Estrase RM, Estrase RN, Estrase RO, Estrase SD, Estrase TL, Lipase CRL-1, Multifect LI lOL, Multifect LI 12L, Lipase Achromobacter, peptidase Rhizopus, BS Lipase, Acid protease, Neutral protease. Alkaline protease or Bacterial protease 6. The process according to claim 4, wherein the enzyme is Protex 6L protease. 7. The process according to claim 1, wherein the step of hydrolyzing the compound ol" formula IV is carried out in the presence of a catalyst and a base and wherein said hydrolysis is performed with or without employing a buffer/co solvent or mixture of buffer/co solvent. 8. The process according to claim 7, wherein the catalyst is dimethyl amino pyridine. 9. The process according to claim 1 or 7, wherein the base is selected from triethylamine, pyridine, alkali hydroxides such as sodium hydroxide or potassium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate. 10. The process according to claim 7, wherein the buffer, co-solvent or mixture of buffer/co solvent is used s about 'J to 60%. 11. The process accordir g to claim 10, wherein the buffer employed is selected from a group consisting of sodium phosphate buffer, potassium phosphate buffer, tris(hydroxymethyl)aminomethane or mixtures thereof 12. The process according to claim 11, wherein the buffer used is in the range of about 10 to 500 mmoles. 13. The process according to claim 1, wherein the hydrolyzing the compound of formula IV is carried out at a controlled pH. 14. The process according to claim 13, wherein the pH is varies between 4 to 8. 15. The process according to claim 1, wherein the hydrolyzing the compound of formula IV is performed at a temperature from about 25" C to 40° C. 16. The process according to claim 1, wherein the acid anhydride is selected from a group consisting of maloni<; anhydride, succinic anhydride, glutaric anhydride or aspartic anhydride. 17. A process for separation of compounds of formula V and VI from a mixture containing the same. wherein R is HO-CO-CH2-CO-, HOCO-CH2-CH2-CO-, HO-CO-CH2-CH2-CH2-CO-, or the like; and b) hydrolyzing Ihe resultant compound of formula VII in presence of a solvent to obtain a corresponding alcohol. 18. The process according to claim 17, wherein the acid anhydride is selected from a group consisting of malonic anhydride, succinic anhydride, glutaric anhydride or aspartic anhydride. 19. The process according to claim 17, wherein the base is selected from triethylamine, pyridine, alkali hydroxides such as sodium hydroxide or potassium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate. 20. The process according to claim 17, wherein the catalyst is dimethyl amino pyridine. 21. The process according to claim 17, wherein the solvents employed are selected from 2-methyl tetrahydrofuran, toluene, hexane, heptane, esters, chlorinated solvents, ethers, ketones or mixture thereof. 22. The process according to claim 21, wherein the solvents are ethylacetate, isopropyl acetate, dichloromethane, chlorobenzene, methyl tertirarybutyl ether, diisopropyl ether, dimethyl formamide, tetrahydrofuran, acetone, propanone, water or mixture thereof. 23. A (S)-(-)-10-acetoj:y-10,11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide prepared by a process according to claim 1, wherein the (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide is characterized by having enantiomeric purity greater than about 99%. 24. The (S)-(-)-10-acetoxy-10,ll-dihydro-5H-dibenz[b,f]azepine-5-carboxamide according to claim 23, wherein the enantiomeric purity is greater than about 99.99%. 25. Intermediate of fonnula VII for producing (S)-(-)-10-acetoxy-10,11- dihydro-5H-dibenz[b,flazepine-5-c£.rboxamide, whererin R is HO-CO-CH2-CO-, HO-CO-CH2-CH2-CO-, HO-CO-CH2-CH2-CH2-C0-, or the like. 26. Intermediates of formula IV for producing (S)-(-)-10-acetoxy-10,11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide wherein the PG is selected from methoxyacetyl, ethyl oxalate or ethyl carbonate. 27. A compound (S)-(-)-10-acetoxy-10,ll-dihydro-5H-dibenz[b,fIazepine-5-carboxamide of formula I having er antiomeric purity greater than about 99% 28. The compound according to claim 27, wherein the enantiomeric purity is greater than about 99.99%.

Documents

Application Documents

# Name Date
1 2463-che-2009 power of attorney 12-10-2009.pdf 2009-10-12
1 2463-CHE-2009-AbandonedLetter.pdf 2018-03-13
2 2463-che-2009 form-5 12-10-2009.pdf 2009-10-12
2 2463-CHE-2009-FER.pdf 2017-09-06
3 2463-che-2009 form-3 12-10-2009.pdf 2009-10-12
3 2463-CHE-2009 AMENDED PAGES OF SPECIFICATION 30-09-2013.pdf 2013-09-30
4 2463-che-2009 form-2 12-10-2009.pdf 2009-10-12
4 2463-CHE-2009 FORM-1 30-09-2013.pdf 2013-09-30
5 2463-che-2009 form-1 12-10-2009.pdf 2009-10-12
5 2463-CHE-2009 FORM-13 30-09-2013.pdf 2013-09-30
6 2463-che-2009 description (complete) 12-10-2009.pdf 2009-10-12
6 2463-CHE-2009 FORM-5 30-09-2013.pdf 2013-09-30
7 2463-che-2009 correspondence-others 12-10-2009.pdf 2009-10-12
7 2463-CHE-2009 CORRESPONDENCE OTHERS 30-09-2013.pdf 2013-09-30
8 2463-che-2009 claims 12-10-2009.pdf 2009-10-12
8 2463-CHE-2009 FORM-3 16-08-2011.pdf 2011-08-16
9 2463-che-2009 form-3 01-11-2010.pdf 2010-11-01
9 2463-che-2009 abstract 12-10-2009.pdf 2009-10-12
10 2463-CHE-2009 FORM-1 05-11-2009.pdf 2009-11-05
11 2463-che-2009 form-3 01-11-2010.pdf 2010-11-01
11 2463-che-2009 abstract 12-10-2009.pdf 2009-10-12
12 2463-CHE-2009 FORM-3 16-08-2011.pdf 2011-08-16
12 2463-che-2009 claims 12-10-2009.pdf 2009-10-12
13 2463-CHE-2009 CORRESPONDENCE OTHERS 30-09-2013.pdf 2013-09-30
13 2463-che-2009 correspondence-others 12-10-2009.pdf 2009-10-12
14 2463-CHE-2009 FORM-5 30-09-2013.pdf 2013-09-30
14 2463-che-2009 description (complete) 12-10-2009.pdf 2009-10-12
15 2463-CHE-2009 FORM-13 30-09-2013.pdf 2013-09-30
15 2463-che-2009 form-1 12-10-2009.pdf 2009-10-12
16 2463-CHE-2009 FORM-1 30-09-2013.pdf 2013-09-30
16 2463-che-2009 form-2 12-10-2009.pdf 2009-10-12
17 2463-CHE-2009 AMENDED PAGES OF SPECIFICATION 30-09-2013.pdf 2013-09-30
17 2463-che-2009 form-3 12-10-2009.pdf 2009-10-12
18 2463-che-2009 form-5 12-10-2009.pdf 2009-10-12
18 2463-CHE-2009-FER.pdf 2017-09-06
19 2463-CHE-2009-AbandonedLetter.pdf 2018-03-13
19 2463-che-2009 power of attorney 12-10-2009.pdf 2009-10-12

Search Strategy

1 2463pat_04-09-2017.pdf