WO2007141798A1 - Procédé de production d'oxcarbazépine via un intermédiaire 11-alcoxy-10-halogéno-dihydroiminostilbène - Google Patents

Procédé de production d'oxcarbazépine via un intermédiaire 11-alcoxy-10-halogéno-dihydroiminostilbène Download PDF

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Publication number
WO2007141798A1
WO2007141798A1 PCT/IN2006/000190 IN2006000190W WO2007141798A1 WO 2007141798 A1 WO2007141798 A1 WO 2007141798A1 IN 2006000190 W IN2006000190 W IN 2006000190W WO 2007141798 A1 WO2007141798 A1 WO 2007141798A1
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WIPO (PCT)
Prior art keywords
formula
oxcarbazepine
alkyl
substituted
process according
Prior art date
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PCT/IN2006/000190
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English (en)
Inventor
Nitin Gupta
Harnam Singh
Pramod Kumar
Sushil Kumar Dubey
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Jubilant Organosys Limited
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Priority to PCT/IN2006/000190 priority Critical patent/WO2007141798A1/fr
Publication of WO2007141798A1 publication Critical patent/WO2007141798A1/fr

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    • 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
    • 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
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11

Definitions

  • This invention in general relates to the process for producing 10-oxo-10,l l-dihydro- 5H-dibenz[ ⁇ ,/]azepine-5-carboxamide (oxcarbazepine).
  • the present invention provides a novel intermediate to produce oxcarbazepine.
  • lO-Oxo-10,1 l-dihydro-5H-dibenz[ ⁇ ,/jazepme-5-carboxamide (oxcarbazepine), a compound of formula I is used in therapy as an anticonvulsant. It has a depressant effect on the central nervous system. Also it has been used for the treatment of psychosomatic disturbances, epilepsy and trigeminal neuralgia and for the treatment of Parkinson's disease and/or Parkinsonian syndromes.
  • Canadian Pat. No. 1,112,241 describes the synthesis of oxcarbazepine from the catalysed re-arrangement of 10,11-epoxycarbazepine [V] 5 which itself can be prepared from carbamezapine [IV] by reaction with m-chloroperbenzoic acid.
  • the main drawback of this process is the use of carbamazepine as a reagent, which is an expensive raw material. Furthermore, the epoxidation reaction is substrate sensitive and thus gives low yields when using conventional epoxidants such as peracetic acid, or it requires remarkable excesses of expensive reagents such as m-chloroperbenzoic acid. Moreover, the rearrangement reaction requires large amounts of costly catalysts and is difficult to control, thus requiring thorough purifications and hence low yields.
  • European Pat. No. 028028 describes the synthesis of oxcarbazepine from 5- cyanoiminostilbene [VII] (by reaction of iminostilbene [VI] with cyanogen chloride) through nitration, reduction and hydrolysis.
  • the main drawback of this process is the use of cyanogen chloride, a difficult to handle toxic gas; nitration using nitrating agents such as N 2 O 3 and N 2 O 4 , which are difficult to use and hydrolysis of cyano group using BF 3 complexes, which are expensive and difficult to handle.
  • Swiss Pat. No. 642,950 describes the synthesis of oxcarbazepine starting from a compound of formula X followed by halogenation, treatment with alkali metal alkoxide and acid hydrolysis.
  • the main drawback of this invention is the use of bromine/chlorine gas for the bromination/chlorination step, which are hazardous and are difficult to handle at commercial scale. Moreover, the conversion of XIII to XIV requires deadly toxic phosgene gas.
  • oxcarbazepine [I] can be prepared by the carbamoylation of MISB [II] using an alkali metal cyanate like sodium cyanate and a relatively strong organic or inorganic acid, followed by the hydrolysis of the enol-ether group under mild acidic conditions.
  • PCT International Application no. WO/2005/066133 to Parkenky et al. discloses the process for preparation of Oxcarbazepine via novel intermediate.
  • the process comprising preparing an intermediate 10-methoxy-5H-dibez[b,fjaze ⁇ ine-5 carbonylchloride from 10-methoxyiminostilbene (II) using bis(trichloromethyl) carbonate (BTC) or triphosgene and an appropriate organic base and further converting said intermediate to the 10-methoxy-5H-dibenz [b,fj azepine-5-carboxamide using ammonia in organic solvent and resultant 10-methoxy-5H-dibenz [b,fj azepine-5- carboxamide is converted into Oxcarbazepine in the presence of lewis acids in appropriate organic solvent.
  • the drawback of this invention is the use of toxic phosgene gas and the multi step reactions to get final product.
  • the present invention provides an industrially feasible process for the preparation of oxcarbazepine via a novel intermediate which involves minimum time consumption, is economical by use of inexpensive reagents and gives overall good yield.
  • a process for producing oxcarbazepine of formula [I] via a novel intermediate wherein said intermediate is prepared by protecting iminostilbene of formula [VI] employing an appropriate protecting reagent to prepare N-substituted iminostilbene [X], alkoxyhalogenating the resultant N-substituted iminostilbene [X] with halogenating agent in presence of lower alcohol to obtain said intermediate of formula [XVIII].
  • halogenating agent is selected from 1,3-dihalo-dimethylhydantoin, N-halosuccinimide, N-haloacetamide or 1,3-haloisocyanuric acid, more preferably dihalodimethyl hydantoin, and wherein said halogenating agent is recoverable and reusable in the process.
  • a process for producing oxcarbazepine of formula [I] via a novel intermediate wherein the process further comprises dehydrohalogenating the obtained intermediate of formula [XVIII] to prepare the compound of formula [XIX], deprotecting the compound of formula [XIX] under basic condition to provide 10-alkoxyiminostilbene of formula [XX] 5 further reacting the resultant 10-alkoxyiminostilbene of formula [XX] with cyanate in presence of organic solvent to provide 10-alkoxycarbamazepine of formula [XXI] and hydrolysing the resultant compound [XXI] in presence of dilute acid to obtain the product Oxcarbazepine of formula [I].
  • a process for producing oxcarbazepine of formula [I] via a novel intermediate wherein the dehydrohalogenation is carried out in the presence of organic base selected from the group comprising of trialkylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo
  • a process for producing oxcarbazepine of formula [I] via a novel intermediate wherein the process avoids production of side products and related impurities during the carboxamidation of 10-alkoxyiminostilbene, further the reaction is carried out in presence of organic solvent selected from an aromatic hydrocarbon or an aliphatic chlorinated solvent, preferably under reflux condition.
  • a novel intermediate, N-substituted- 10-halo- 11 -alkoxy- 10, 11 -dihydro-5H-dibenzo[ ⁇ j /] azepine of formula [XVIII] for preparing 10-alkoxyiminostilbene wherein said intermediate of formula [XVIII] is dehydrohalogenated to prepare the compound of formula [XIX], which is deprotected under basic condition to provide 10- alkoxyiminostilbene of formula [XX], a useful intermediate to prepare Oxcarbazepine of formula [I], wherein said intermediate 10-alkoxyiminostilbene of formula [XX] is further reacted with cyanate in presence of organic solvent to provide 10- alkoxycarbamazepine of formula [XXI] which is followed by hydrolysis in presence of dilute acid to obtain the product Oxcarbazepine of formula [I].
  • the process comprises protecting iminostilbene of formula [VI] employing an appropriate protecting reagent to prepare N-substituted iminostilbene [X], alkoxyhalogenating the resultant N-substituted iminostilbene [X] with halogenating agent in presence of lower alcohol to obtain said intermediate of formula [XVIII], dehydrohalogenating the said intermediate of formula [XVIII] to prepare the compound of formula [XIX], deprotecting the compound of formula [XIX] under basic condition to provide 10-alkoxyiminostilbene of formula [XX], which is further converted to the product Oxcarbazepine of formula [I] according to the present invention.
  • the disclosed embodiment of the present invention deals with a process for the preparation of novel intermediate [XVIII], useful in preparing anti-convulsant oxcarbazepine [1], which is economically viable and cost effective and thus obviates the disadvantages mentioned in prior art.
  • R is C 1 -C 3 alkyl chain
  • P is -(CO)alkyl, -CHO 5 -(CO)Oalkyl, -Fmoc, -(SO 2 )R 1 alkyl is C 1 -C 4 alkyl chain
  • R 1 is C 1 -C 4 alkyl, substituted or unsubstituted aromatic ring and X is Cl 5 Br or I
  • the subject of the present invention is a process of preparing oxcarbazepine of formula [I], the process comprising:
  • the process may be performed via the isolation and the optional purification of the individual intermediates of the formula X and XIX 5 or, preferably by minimizing this procedure i.e. working directly on the crude reaction product from the partial worked up preceding steps as illustrated in the experimental section.
  • Protecting the nitrogen of said iminostilbene of formula [VI] is carried out by acylation, wherein acylation is performed employing an acylating agent, preferably formaldehyde, acetic anhydride, acetyl chloride, acetic acid or sodium acetate, most preferably formaldehyde.
  • acylating agent preferably formaldehyde, acetic anhydride, acetyl chloride, acetic acid or sodium acetate, most preferably formaldehyde.
  • the molar ratio of acylating agent relative to the compound of formula [VI] used in the process is preferably in the range of 0.4:1 and 0.6:1 and more preferably in the range of about 0.5:1.
  • the reaction is preferably performed in the temperature range of 80-140°C and more preferably in the temperature range of 90- 100 0 C.
  • reaction mixture is subjected to minimum workup by removing the volatiles by distillation and is used directly for alkoxyhalogenation reaction without further purification.
  • the nitrogen atom of compound of formula VI can also be protected using 9-fluorenylmethyl chloroformate or aryl sulphonylchlorides.
  • Alkoxyhalogenation reaction according to the present invention is performed at a temperature of about -20°C to 20°C, preferably about 2-10°C.
  • the halogenating agent used in the process is selected from dihalodimethyl hydantoin, N-halosuccinimide, 1,3- dihaloisocyanuric acid or N-haloacetamide, preferably dihalodimethyl hydantoin in the molar ratio of 1:0.6 and 1:0.4, preferably in the range of about 1 :0.5.
  • the lower alcohol used in the process is preferably methanol.
  • hydantoin is formed, which can be recovered from the mother liquor and reused after recrystallization from water.
  • Dehydrohalogenating the intermediate of formula [XVII] according the present invention is carried out in presence of organic bases, wherein said base is selected from trialkylamine, pyridine, l,8-diazabicyclo[2.2.2]octane, l,5-diazabicyclo[4.3.0]non-5- ene, l,8-diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, N-methylpiperidine or tetramethylguanidine, preferably triethylamine.
  • organic bases wherein said base is selected from trialkylamine, pyridine, l,8-diazabicyclo[2.2.2]octane, l,5-diazabicyclo[4.3.0]non-5- ene, l,8-diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, N-methylpiperidine or tetramethylgu
  • reaction is performed in presence of aprotic solvents at the refluxing temperature, wherein said solvent is selected from toluene, xylene, benzene or ethyl benzene, preferably toluene.
  • aprotic solvents at the refluxing temperature, wherein said solvent is selected from toluene, xylene, benzene or ethyl benzene, preferably toluene.
  • the base is taken in the molar ratio of 1:1.5 to 1:2.2, preferably in the range of 1:2.
  • the base used with the halogen forms the solid amine salt, which can be filtered and reused in the process.
  • Deprotecting the resultant compound of formula [XIX] according to the present invention is carried out by deacylation of said compound in presence of base in the molar ratio of about 1:2 to about 1:6, preferably in the ratio of about 1:1.4 and a solvent, wherein said base is selected from alkali metal alkoxide or inorganic base consisting of sodium methoxide, potassium or sodium tertiary butoxide, potassium or sodium hydroxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium peroxide, sodium or potassium hydride, preferably sodium methoxide and wherein said solvent is selected from the group comprising N,N-dimethylformamide, dimethylsulphoxide, N,N-dimetylacetamide, N-methylpyrrolidone, dimethylimidazolidone, C 1 -C 5 alcoholic solvents, toluene, xylene or acetonitrile.
  • phase transfer catalyst is used in the reaction. Further, said reaction is
  • Carboxamidation of 10-alkoxyiminostilbene comprises reacting 10-alkoxyiminostilbene with HOCN in presence of organic medium, wherein the disclosed cyanates include sodium or potassium cyanate, preferably sodium cyanate and said organic medium is selected from an aromatic hydrocarbon solvent or an aliphatic chlorinated solvent such as benzene, toluene, xylene or dichloromethane.
  • the generation of cyanate is performed in situ by the reaction of alkali metal cyanate with a mild acidic reagent.
  • the acidic reagent is preferably a weak acid, such as an aromatic acid.
  • Preferred aromatic acids include weak non-aliphatic organic acids such as benzoic acid or halo substituted benzoic acids; suitable substituents being halo especially chloro e.g. para-chlorobenzoic acid.
  • Excess molar quantity of the weak acid is preferably used in comparison to 10- alkoxyiminostilbene [XX], in the range of from 2 to 10 molar excess, preferably about 5 to 8 times.
  • the reaction is carried out employing an organic medium, preferably under reflux conditions.
  • the organic medium is selected from aromatic hydrocarbon solvent or aliphatic chlorinated solvent, preferably benzene, toluene, xylene or dichloromethane.
  • the oxcarbazepine can also be prepared from the said 10-alkoxyiminostilbene using any prior known processes.
  • the intermediate [XVIII] was characterized by 1 H NMR, 13 C NMR, IR and LC-MS spectroscopy.
  • the crude [XXI] was taken in a RB flask and methanol (600 ml) was added. The reaction mixture was heated to reflux. The reaction mixture was cooled, methanol was distilled off and toluene (50 ml) was added and further distilled. The residual [XXI] was cooled and toluene (500 ml) was added and stirred. Water was added followed by addition of cone. HCl. The reaction mixture was heated at 75-80°C. The reaction mixture was cooled and the crude oxcarbazepine [I] was filtered, washed with toluene, 5% NaHCO 3 and DM water and vacuum dried to give crude oxcarbazepine of formula
  • reaction mixture was filtered through Hyflo bed and washed with methanol and dichloromethane mixture (1:1). The solvent was distilled to residual volume of 1000 mL. The reaction mixture was cooled and maintained. The reaction mixture was filtered through buchner funnel and washed with methanol and dried under vacuum at 50-60°C to give pure oxcarbazepine (90 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé économiquement viable et rentable de synthèse de l'oxcarbazépine de formule (I) via un nouvel intermédiaire de formule (XVIII).
PCT/IN2006/000190 2006-06-07 2006-06-07 Procédé de production d'oxcarbazépine via un intermédiaire 11-alcoxy-10-halogéno-dihydroiminostilbène WO2007141798A1 (fr)

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PCT/IN2006/000190 WO2007141798A1 (fr) 2006-06-07 2006-06-07 Procédé de production d'oxcarbazépine via un intermédiaire 11-alcoxy-10-halogéno-dihydroiminostilbène

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PCT/IN2006/000190 WO2007141798A1 (fr) 2006-06-07 2006-06-07 Procédé de production d'oxcarbazépine via un intermédiaire 11-alcoxy-10-halogéno-dihydroiminostilbène

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102807528A (zh) * 2012-08-07 2012-12-05 常州华生精细化工有限公司 10-甲氧基亚氨基芪的制备方法
WO2013008194A2 (fr) 2011-07-13 2013-01-17 Ranbaxy Laboratories Limited Procédé de préparation et de purification d'acétate d'eslicarbazépine et de ses intermédiaires
WO2014049550A1 (fr) 2012-09-26 2014-04-03 Ranbaxy Laboratories Limited Procédé de préparation d'oxcarbazépine et son utilisation en tant qu'intermédiaire dans la préparation d'acétate d'eslicarbazépine
WO2024109438A1 (fr) * 2022-11-23 2024-05-30 浙江华洋药业有限公司 Procédé de préparation de 10-méthoxyiminostilbène de faible impureté ayant une pureté élevée

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH642950A5 (en) * 1979-10-30 1984-05-15 Ciba Geigy Ag Process for the preparation of 10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide
WO1996021649A1 (fr) * 1995-01-13 1996-07-18 Trifarma, S.R.L. PROCEDE DE PREPARATION DU 10-OXO-10,11-DIHYDRO-5H-DIBENZ(b,f)AZEPIN-5-CARBOXAMIDE

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH642950A5 (en) * 1979-10-30 1984-05-15 Ciba Geigy Ag Process for the preparation of 10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide
WO1996021649A1 (fr) * 1995-01-13 1996-07-18 Trifarma, S.R.L. PROCEDE DE PREPARATION DU 10-OXO-10,11-DIHYDRO-5H-DIBENZ(b,f)AZEPIN-5-CARBOXAMIDE

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013008194A2 (fr) 2011-07-13 2013-01-17 Ranbaxy Laboratories Limited Procédé de préparation et de purification d'acétate d'eslicarbazépine et de ses intermédiaires
CN102807528A (zh) * 2012-08-07 2012-12-05 常州华生精细化工有限公司 10-甲氧基亚氨基芪的制备方法
WO2014049550A1 (fr) 2012-09-26 2014-04-03 Ranbaxy Laboratories Limited Procédé de préparation d'oxcarbazépine et son utilisation en tant qu'intermédiaire dans la préparation d'acétate d'eslicarbazépine
WO2024109438A1 (fr) * 2022-11-23 2024-05-30 浙江华洋药业有限公司 Procédé de préparation de 10-méthoxyiminostilbène de faible impureté ayant une pureté élevée

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