EP1678140A2 - Neues verfahren zur herstellung von 10-oxo-10,11-dihydro-5h-dibenz[ b,f] azepin-5-carbonsäureamid (oxcarbazepin) über das 10-methoxy-5h-dibenz[b,f]azepin-5-carbonylchlorid-zwischenprodukt - Google Patents
Neues verfahren zur herstellung von 10-oxo-10,11-dihydro-5h-dibenz[ b,f] azepin-5-carbonsäureamid (oxcarbazepin) über das 10-methoxy-5h-dibenz[b,f]azepin-5-carbonylchlorid-zwischenproduktInfo
- Publication number
- EP1678140A2 EP1678140A2 EP04820974A EP04820974A EP1678140A2 EP 1678140 A2 EP1678140 A2 EP 1678140A2 EP 04820974 A EP04820974 A EP 04820974A EP 04820974 A EP04820974 A EP 04820974A EP 1678140 A2 EP1678140 A2 EP 1678140A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- dibenz
- azepine
- methoxy
- novel process
- oxcarbazepine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 30
- 229960001816 oxcarbazepine Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- ANRYPESGCUZAHS-UHFFFAOYSA-N 5-methoxybenzo[b][1]benzazepine-11-carbonyl chloride Chemical compound COC1=CC2=CC=CC=C2N(C(Cl)=O)C2=CC=CC=C12 ANRYPESGCUZAHS-UHFFFAOYSA-N 0.000 title claims description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 19
- ZKHZWXLOSIGIGZ-UHFFFAOYSA-N 5-methoxy-11h-benzo[b][1]benzazepine Chemical compound COC1=CC2=CC=CC=C2NC2=CC=CC=C12 ZKHZWXLOSIGIGZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000002841 Lewis acid Substances 0.000 claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 7
- 150000007530 organic bases Chemical class 0.000 claims abstract description 6
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 5
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- -1 aromatic tertiary amines Chemical class 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract 3
- 238000002955 isolation Methods 0.000 claims abstract 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- PIZOFBKQWNPKDK-UHFFFAOYSA-N 5-methoxybenzo[b][1]benzazepine-11-carboxamide Chemical compound COC1=CC2=CC=CC=C2N(C(N)=O)C2=CC=CC=C12 PIZOFBKQWNPKDK-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002091 cationic group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims 1
- BSFODEXXVBBYOC-UHFFFAOYSA-N 8-[4-(dimethylamino)butan-2-ylamino]quinolin-6-ol Chemical compound C1=CN=C2C(NC(CCN(C)C)C)=CC(O)=CC2=C1 BSFODEXXVBBYOC-UHFFFAOYSA-N 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- ZFXVFMBOFIEPII-UHFFFAOYSA-N 1h-azepine-4-carboxamide Chemical compound NC(=O)C1=CC=CNC=C1 ZFXVFMBOFIEPII-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 3
- 229960000623 carbamazepine Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- LCGTWRLJTMHIQZ-UHFFFAOYSA-N 5H-dibenzo[b,f]azepine Chemical compound C1=CC2=CC=CC=C2NC2=CC=CC=C21 LCGTWRLJTMHIQZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- RDUUENFQVLPVCO-UHFFFAOYSA-N N#CN=C1CC=CC(C=CC=2C=CC=CC=2)=C1 Chemical compound N#CN=C1CC=CC(C=CC=2C=CC=CC=2)=C1 RDUUENFQVLPVCO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- YEJAJYAHJQIWNU-UHFFFAOYSA-N azelastine hydrochloride Chemical compound Cl.C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 YEJAJYAHJQIWNU-UHFFFAOYSA-N 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- ZRWWEEVEIOGMMT-UHFFFAOYSA-N carbamazepine-10,11-epoxide Chemical compound NC(=O)N1C2=CC=CC=C2C2OC2C2=CC=CC=C12 ZRWWEEVEIOGMMT-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940086542 triethylamine Drugs 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)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1108MU2003 | 2003-10-20 | ||
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1678140A2 true EP1678140A2 (de) | 2006-07-12 |
Family
ID=34746667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP04820974A Withdrawn EP1678140A2 (de) | 2003-10-20 | 2004-10-15 | Neues verfahren zur herstellung von 10-oxo-10,11-dihydro-5h-dibenz[ b,f] azepin-5-carbonsäureamid (oxcarbazepin) über das 10-methoxy-5h-dibenz[b,f]azepin-5-carbonylchlorid-zwischenprodukt |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1678140A2 (de) |
| WO (1) | WO2005066133A2 (de) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2471666C (en) | 2004-06-18 | 2009-10-13 | Apotex Pharmachem Inc. | An improved 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 |
| US20150232426A1 (en) | 2012-09-26 | 2015-08-20 | Ranbaxy Laboratories Limited | Process for the preparation of oxcarbazepine and its use as intermediate in the preparation of eslicarbazepine acetate |
| CN115650918A (zh) * | 2022-11-23 | 2023-01-31 | 浙江华洋药业有限公司 | 一种高纯度低杂质10-甲氧基亚氨基芪的制备工艺 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH500196A (de) * | 1969-03-10 | 1970-12-15 | Ciba Geigy Ag | Verfahren zur Herstellung von neuen Azepinderivaten |
| 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 |
| IT1272897B (it) * | 1995-01-13 | 1997-07-01 | I F C Iniziative Finanziaarie | Processo per la produzione di 10-oxo-10,11-diidro-sh- -dibenz(b,f) azepin-5-carbossiammide |
-
2004
- 2004-10-15 WO PCT/IN2004/000322 patent/WO2005066133A2/en not_active Ceased
- 2004-10-15 EP EP04820974A patent/EP1678140A2/de not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005066133A3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005066133A2 (en) | 2005-07-21 |
| WO2005066133A3 (en) | 2005-10-06 |
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