WO2005066133A2 - NOVEL PROCESS FOR PREPARATION OF 10-OXO-10, 11-DIHYDRO-5H-DIBENZ [b,f]AZEPINE-5-CARBOXAMIDE (OXCARBAZEPINE) VIA INTERMEDIATE, 10-METHOXY-5H-DIBENZ[b,f] AZEPINE-5-CARBONYLCHLORIDE - Google Patents
NOVEL PROCESS FOR PREPARATION OF 10-OXO-10, 11-DIHYDRO-5H-DIBENZ [b,f]AZEPINE-5-CARBOXAMIDE (OXCARBAZEPINE) VIA INTERMEDIATE, 10-METHOXY-5H-DIBENZ[b,f] AZEPINE-5-CARBONYLCHLORIDE Download PDFInfo
- Publication number
- WO2005066133A2 WO2005066133A2 PCT/IN2004/000322 IN2004000322W WO2005066133A2 WO 2005066133 A2 WO2005066133 A2 WO 2005066133A2 IN 2004000322 W IN2004000322 W IN 2004000322W WO 2005066133 A2 WO2005066133 A2 WO 2005066133A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dibenz
- azepine
- methoxy
- novel process
- oxcarbazepine
- Prior art date
Links
- 0 C*CCC1c(cccc2)c2/C=C(/C(I)=O)\c2ccccc2C1 Chemical compound C*CCC1c(cccc2)c2/C=C(/C(I)=O)\c2ccccc2C1 0.000 description 2
- ZKHZWXLOSIGIGZ-UHFFFAOYSA-N COC1=Cc(cccc2)c2Nc2ccccc12 Chemical compound COC1=Cc(cccc2)c2Nc2ccccc12 ZKHZWXLOSIGIGZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
Definitions
- the present invention relates to an improved process for preparation of 10-methoxy- 5H-dibenz[b,fjazepine-5-carbonyl chloride from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) without the use of phosgene and its further conversion to 10-oxo-IO, 11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) without the use of strong mineral acids.
- Oxcarbazepine is an anticonvulsant drug used as an anti-epileptical agent in treatment of AIDS-related neural disorders and for treatment of Parkinson's disease
- US Patent 3462775 describes the preparation of oxcarbazepine from 10-methoxy iminostilbene by phosgenation in toluene, followed by amidation (ethanol and ammonia) and hydrolysis in acidic medium to get e desired product (Scheme 1 ).
- the phosgenation is carried out at relatively high temperatures of around 95°C and the hydrochloric acid produced leads to the formation of undesirable impurities.
- the process uses phosgene gas, which is toxic and hazardous requiring extreme precaution making this process commercially unattractive.
- Canadian Patent 112 241 describes an alternate preparation of oxcarbazepine from the catalysed re-arrangement of 10,11-epoxycarbamazepine, prepared from carbamazepine by reaction with m-chloroperbenzoic acid (CPBA) (Scheme-2). Starting with Carbamazepine, which is an expensive raw material, the conversion to its epoxide is poor in quality and yield.
- CPBA m-chloroperbenzoic acid
- EP Patent Application 028028 discloses a process involving nitration of 5- cyanoiminostilbene followed by reduction and hydrolysis (Scheme-3).
- Scheme 3 discloses a process involving nitration of 5- cyanoiminostilbene followed by reduction and hydrolysis.
- the drawback of the process is in the preparation of the 5- cyanoiminostilbene itself, which can be made from iminostilbene and cyanogen chloride. The latter is also toxic, hazardous and difficult to handle.
- Swiss Patent No. 642 950 suggests hydrolysis of the 10-chloro-5H-dibenz [ b,f ] azepin-5-carboxamide using concentrated sulphuric acid to form the oxcarbazepine. However the yields are poor.
- the main object of the invention is to provide a cost effective, safe and high yielding process for the production of 10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride, from 10-methoxy-5H-dibenz [b,f]azepine (10-methoxy iminostilbene) without the use of phosgene gas as is practiced in the prior art an important intermediate for the synthesis of 10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide
- Another object of the invention is o develop a process thaf can be carrie out at relatively lower temperatures to avoid the formation of any undesirable impurities.
- Yet another object of the invention is to provide a cost effective process using easily available raw materials.
- Yet another object of the invention is to provide a process for the conversion of the intermediate 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide to 10-oxo-IO, 11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) using mild reagents such as methane sulphonic acid, para toluene sulphonic acid, Lewis acids,_caiionic resins, etc.
- mild reagents such as methane sulphonic acid, para toluene sulphonic acid, Lewis acids,_caiionic resins, etc.
- reaction (scheme 4) comprises steps
- 10-Methoxyiminostilbene is dissolved in a solvent and cooled below 10°C and bis- (trichloromethyl) carbonate (BTC) is added.
- BTC bis- (trichloromethyl) carbonate
- An organic base is slowly added to the above solution over a period ranging fro-3-24-hours maintainiRg-the ; temperature -below- 10°C till the reaction goes to completion.
- the reaction mixture- is allowed to -warm - up to- around room temperature- and maintained at this temperature till the completion of the reaction as monitored by TLC/HPLC.
- the reaction mixture is quenched in water and the layers are allowed to separate.
- the solvent used in the carbonyl chloride preparation step may be selected from chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1 , 1 ,1 ,-trichloroethane, trichloroethylene etc. or aromatic hydrocarbon solvent such as toluene, xylene, chlorobenzene, etc. or aprotic solvents including Dimethyl formamide, dimethyl acetamide,- N-methyl pyrrolidine and acetonitrile.
- the organic base used in this step is selected from aliphatic/ aromatic tertiary arnines such as triethyl amine/ diethyl aniline, pyridine, picoline etc.
- initial addition of the base may be followed by the addition of BTC.
- the time of the addition of base ranges from .3 -8 hrs, the temperature at which the base is added may range upto 30°C preferably below 10°C and most preferably from 0° to + ⁇ °C.
- the reaction period may vary from about 3 hours to about 10 hours.
- the molar ratio of 10-methoxy iminostilbene to BTC is 1 :0.34-0.5.
- the molar ratio of 10-methoxy iminostilbene verses the base is 1: 1-1.5.
- the solvents preferred in the amidation reaction are selected from solvents like acetone, methyl cellosolve, methanol, ethanol, isopropyl alcohol, dimethyl formamide, dimethlacetamide, N-methyl pyrrolidone or aromatic.solvents like toluene, xylene etc.
- the solvent used in the final oxo preparation step ay be selected from chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1 , 1 ,1,-trichloroethane, trichloroethylene etc or aromatic hydrocarbon solvent such as toluene, xylene, chlorobenzene, etc. or aprotic solvents including dimethyl formamide, dimethyl acetamide, N-methyl pyirrolidine and acetonitrile.
- chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1 , 1 ,1,-trichloroethane, trichloroethylene etc or aromatic hydrocarbon solvent such as toluene, xylene, chlorobenzene, etc. or aprotic solvents including dimethyl formamide, dimethyl acetamide, N-methyl pyirrolidine and acetonitrile.
- the Lewis acids used in this are selected from! cationic resins, para- toluene sulfonic acid, aluminium chloride, etc.
- the temperature at which the reaction may be carried out may vary from 25 to 80°C, preferably between 50 to 70°C
- the present invention obviates the use of phosgene gas in the preparation of 10- methoxy ⁇ -dibenz[b,f]azepine-£ carbonyl chloride from 10 ⁇ methoxy-5H- dibe ⁇ ,f]azepine (10-methgxy iminostilbene).
- the invention provide a process for the conversion of the intermediate 10-methoxy-5H-dibenz[b,f]azepine-5- carboxami ⁇ e to 10-oxo-10,11-dihydro-5H-dibenz [b,f] azepine-5-carboxamide (oxcarbazepine) without the use harsh conditions and strong mineral acids thereby obtaining high quality oxcarbazepine in a cost effective manner from easily available raw materials.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04820974A EP1678140A2 (en) | 2003-10-20 | 2004-10-15 | Novel process for preparation of 10-oxo-10, 11-dihydro-5h-dibenz [b,f]azepine-5-carboxamide (oxcarbazepine) via intermediate, 10-methoxy-5h-dibenz [b,f] azepine-5-carbonylchloride |
US10/576,546 US20070032647A1 (en) | 2004-10-15 | 2004-10-15 | Novel process for preparation of 10-oxo-10, 11-dihydro-5h-dibenz [b,f] azepine-5-carbox- amide (oxcarbazepine) via intermediate, 10-methoxy-5h-debenz[b,f] azepine-5-carbonyl- chloride |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1108/MUM/2003 | 2003-10-20 | ||
IN1108MU2003 | 2003-10-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005066133A2 true WO2005066133A2 (en) | 2005-07-21 |
WO2005066133A3 WO2005066133A3 (en) | 2005-10-06 |
Family
ID=34746667
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2004/000322 WO2005066133A2 (en) | 2003-10-20 | 2004-10-15 | NOVEL PROCESS FOR PREPARATION OF 10-OXO-10, 11-DIHYDRO-5H-DIBENZ [b,f]AZEPINE-5-CARBOXAMIDE (OXCARBAZEPINE) VIA INTERMEDIATE, 10-METHOXY-5H-DIBENZ[b,f] AZEPINE-5-CARBONYLCHLORIDE |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP1678140A2 (en) |
WO (1) | WO2005066133A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7125987B2 (en) | 2004-06-18 | 2006-10-24 | Apotex Pharmachem Inc. | Process for the preparation of oxcarbazepine and related intermediates |
WO2013008194A2 (en) | 2011-07-13 | 2013-01-17 | Ranbaxy Laboratories Limited | Process for the preparation and purification of eslicarbazepine acetate and intermediates thereof |
WO2014049550A1 (en) | 2012-09-26 | 2014-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of oxcarbazepine and its use as intermediate in the preparation of eslicarbazepine acetate |
CN115650918A (en) * | 2022-11-23 | 2023-01-31 | 浙江华洋药业有限公司 | Preparation process of high-purity low-impurity 10-methoxyiminostilbene |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2011087A1 (en) * | 1969-03-10 | 1970-09-24 | J.R. Geigy AG, Basel (Schweiz) | Process for the preparation of a new azepine derivative s |
US5808058A (en) * | 1995-01-13 | 1998-09-15 | Trifarma S.R.L. | Process for the preparation of 10-OXO-10, 11-dihydro-5H-dibenz (b,f) azepin-5-carboxamide |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUT63389A (en) * | 1991-12-27 | 1993-08-30 | Alkaloida Vegyeszeti Gyar | Improved process for producing 5-carbamoyl-10-oxo-10,11-dihydro-5h-dibenz/b,f/azepine |
-
2004
- 2004-10-15 EP EP04820974A patent/EP1678140A2/en not_active Withdrawn
- 2004-10-15 WO PCT/IN2004/000322 patent/WO2005066133A2/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2011087A1 (en) * | 1969-03-10 | 1970-09-24 | J.R. Geigy AG, Basel (Schweiz) | Process for the preparation of a new azepine derivative s |
US5808058A (en) * | 1995-01-13 | 1998-09-15 | Trifarma S.R.L. | Process for the preparation of 10-OXO-10, 11-dihydro-5H-dibenz (b,f) azepin-5-carboxamide |
Non-Patent Citations (1)
Title |
---|
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HAASZ, FERENC ET AL: "Improved process for producing 5-carbamoyl-10-oxo-10,11-dihydro-5H- dibenz[b,f]azepine" XP002334714 retrieved from STN Database accession no. 1994:164010 & HU 63 389 A2 (ALKALOIDA VEGYESZETI GYAR, HUNG.) 30 August 1993 (1993-08-30) * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7125987B2 (en) | 2004-06-18 | 2006-10-24 | Apotex Pharmachem Inc. | Process for the preparation of oxcarbazepine and related intermediates |
WO2013008194A2 (en) | 2011-07-13 | 2013-01-17 | Ranbaxy Laboratories Limited | Process for the preparation and purification of eslicarbazepine acetate and intermediates thereof |
WO2014049550A1 (en) | 2012-09-26 | 2014-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of oxcarbazepine and its use as intermediate in the preparation of eslicarbazepine acetate |
CN115650918A (en) * | 2022-11-23 | 2023-01-31 | 浙江华洋药业有限公司 | Preparation process of high-purity low-impurity 10-methoxyiminostilbene |
Also Published As
Publication number | Publication date |
---|---|
WO2005066133A3 (en) | 2005-10-06 |
EP1678140A2 (en) | 2006-07-12 |
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