- Selective Oxidation of Benzylic sp3C-H Bonds using Molecular Oxygen in a Continuous-Flow Microreactor
-
Selective aerobic oxidation of benzylic sp3 C-H bonds to generate the corresponding ketones was achieved under continuous-flow conditions. The catalysts N-hydroxyphthalimide (NHPI) and tert-butyl nitrite (TBN) as the precursor of the radical under aerobic conditions motivated this process. Flow microreactors operating under optimized conditions enabled this oxidation with higher efficiency and a shortened reaction time of 54 s (total time was 10 min), which was improved 466 times compared with the batch parallel reaction (7.0 h). Notably, the catalyst and solvent recycling (92.6 and 94.5%) and scale-up experiments (0.87 g h-1 in 28 h) demonstrated the practicability of the protocol. The high product selectivity and functional group tolerance of the process allowed the production of ketones in yields of 41.2 to 90.3%. To reveal the versatility and applicability of this protocol, the late-stage modification of an antiepileptic drug to obtain oxcarbazepine was further conducted.
- Ma, Cunfei,Meng, Qingwei,Tang, Xiaofei,Yu, Zongyi,Yun, Lei,Zhao, Jingnan
-
p. 1612 - 1618
(2021/07/21)
-
- Synthesis and characterization of potential impurities of Oxcarbazepine drug substance: An antiepileptic agent
-
Oxcarbazepine is a drug substance used to treat epilepsy. During its bulk synthesis of various impurities formation will be observed. Herein we describe the formation, synthesis and characterization of four potential impurities, namely, N-acetyl Oxcarbazepine, N-formyl Oxcarbazepine, N-carbamoyl Oxcarbazepine, and Oxcarbazepine dimer. These impurities are listed in several Pharmacopoeias and the control of these impurities below the threshold level is essential. Our study will be a guide for making these reference standards.
- Velugula, Siva Rama Kasibabu,Reddy, Aaramadaka Sunil Kumar,Misra, Nimesh Chandra,Reddy, Pindi Santhosh,Chavakula, Ramadas,Guduri, Anil Kumar,DouglasSanasi, Paul
-
p. 1581 - 1587
(2021/05/06)
-
- Preparation method of oxcarbazepine
-
The invention discloses a preparation method of oxcarbazepine, which comprises the following step: oxidizing 10, 11-dihydrocarbazepine with sodium hypochlorite under the combined action of ruthenium chloride, copper chloride and a phase transfer catalyst to obtain oxcarbazepine.
- -
-
Paragraph 0004; 0007-0009
(2020/07/08)
-
- Intermediate compound, carbamazepine and derivative thereof as well as preparation method of oxcarbazepine and derivative thereof
-
The invention provides an intermediate compound, carbamazepine and a derivative thereof as well as a preparation method of oxcarbazepine and a derivative thereof. 2-substituted aminophenylacetate or 2-substituted aminophenylacetonitrile and 2-halobenzonitrile are used as raw materials, substitution reaction, intramolecular condensation reaction, hydrolysis and hydrochloric acid acidification are carried out to obtain the oxcarbazepine and the derivative 5-substituent-10-oxa-10, 11-dihydro-5H-dibenzo [b, f] aza thereof, and the derivative of the oxcarbazepine can be used as a raw material to prepare the carbamazepine and the derivative 5-substituted iminostilbene thereof, an intermediate compound iminostilbene and intermediate compounds 5-substituted-10-methoxyiminostilbene and 10-methoxyiminostilbene. The raw materials used in the method are cheap and easy to obtain, and the cost is low; the preparation method is simple, conditions are easy to realize, the method is simple, convenientand safe to operate, and the process flow is short; the production amount of three wastes is small, and thus, the method is environmentally friendly; and a target product has high yield and purity, and is suitable for industrial production.
- -
-
Paragraph 0109; 0112-0115
(2019/12/25)
-
- Preparation method of 10, 11-dihydrogen-10oxo-5H-dibenzo[b,f]azepine-5-formamide
-
The invention relates to a preparation method of 10, 11-dihydrogen-10oxo-5H-dibenzo[b,f] azepine-5-formamide. The preparation method is characterized by comprising the following steps: dissolving 10,11-dihydrogen-10-methoxyl-5H-dibenzo[b,f]azepine-5-formamide in a mixed solvent, then pumping into a tubular reactor by virtue of a metering pump, remaining in the tubular reactor for 1 to 2 hours, wherein the reaction temperature in the tube is 40 to 100 DEG C, collecting a reaction solution, distilling concentrating to remove partial solvent and water, then cooling at 0 to 10 DEG C to precipitatea product, filtering, and drying to obtain a finished product, 10, 11-dihydrogen-10oxo-5H-dibenzo[b,f]azepine-5-formamide. The preparation method provided by the invention has the advantages that thepurity of the finished product can be improved, the industrialized production is easy to implement, the cost is low, and the preparation method is environmentally friendly.
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Paragraph 0003; 0012-0014
(2018/06/26)
-
- Synthetic method of oxcarbazepine
-
The invention relates to a synthetic method of oxcarbazepine. According to the method, the oxcarbazepine is prepared from iminodibenzyl as a raw material through formyl chlorination, dihalogenated dehydrohalogenation, ammonification and hydrolyzation; a product obtained after formyl chlorination is iminodibenzyl-5-carbonyl chloride, wherein the dihalogenated dehydrohalogenation process specifically comprises the step that the iminodibenzyl-5-carbonyl chloride and a halogenating reagent react for 3-6 h at the temperature ranging from 80 DEG C to the reflux temperature in the presence of an organic solvent and an initiating agent to obtain a disubstituted halogenated product, then the disubstituted halogenated product reacts for 8-16 h at the reflux temperature to be subjected to dehydrohalogenation to obtain 10-halo-5H-dibenzoazepine-5-formyl chloride. The method has the advantages that starting materials are low in price and easy to obtain; the processing step is short; the yield is high; and the cost is low.
- -
-
Paragraph 0016
(2017/08/31)
-
- COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
-
The invention relates to the compounds of formula I and formula IA or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I and formula IA; and methods for treating or preventing neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder (ADHD), schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, Myotonia congenita and post-traumatic stress disorder.
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Paragraph 0135-0136
(2016/06/01)
-
- PROCESS FOR THE PREPARATION AND PURIFICATION OF ESLICARBAZEPINE ACETATE AND INTERMEDIATES THEREOF
-
The present invention provides a novel process for the preparation of 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide, commonly known as oxcarbazepine, which is a medicament and a useful intermediate in the preparation of eslicarbazepine acetate. The present invention further provides a process for the preparation and purification of eslicarbazepine acetate.
- -
-
Paragraph 0105
(2015/03/16)
-
- Carbamazepine derivatives with P2X4 receptor-blocking activity
-
Antagonists for the P2 receptor subtype P2X4, an ATP-activated cation channel receptor, have potential as novel drugs for the treatment of neuropathic pain and other inflammatory diseases In the present study, a series of 47 carbamazepine derivatives including 32 novel compounds were designed, synthesized, and evaluated as P2X4 receptor antagonists Their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor was determined Additionally, species selectivity (human, rat, mouse) and receptor subtype selectivity (P2X4 vs P2X1, 2, 3, 7) were investigated for selected derivatives The most potent compound of the present series, which exhibited an allosteric mechanism of P2X4 inhibition, was N,N-diisopropyl-5H-dibenz[b,f]azepine-5-carboxamide (34, IC50 of 3.44 μM) The present study extends the so far very limited knowledge on structure-activity relationships of P2X4 receptor antagonists
- Tian, Maoqun,Abdelrahman, Aliaa,Weinhausen, Stephanie,Hinz, Sonja,Weyer, Stefanie,Dosa, Stefan,El-Tayeb, Ali,Müller, Christa E.
-
p. 1077 - 1088
(2014/02/14)
-
- An efficient synthesis for eslicarbazepine acetate, oxcarbazepine, and carbamazepine
-
Efficient methods have been developed for the synthesis of three active pharmaceutical ingredients (APIs) carbamazepine (Tegretol) 1, oxcarbazepine (Trileptal) 2, and eslicarbazepine acetate (Exalief) 3 by employing enantioselective reduction and carboxamidation reaction.
- Ravinder,Rajeshwar Reddy,Sridhar,Murali Mohan,Srinivas, Katkam,Panasa Reddy,Bandichhor, Rakeshwar
-
supporting information
p. 2841 - 2844
(2013/06/26)
-
- PROCESS FOR THE PREPARATION AND PURIFICATION OF ESLICARBAZEPINE ACETATE AND INTERMEDIATES THEREOF
-
The present invention provides a novel process for the preparation of 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide, commonly known as oxcarbazepine, which is a medicament and a useful intermediate in the preparation of eslicarbazepine acetate. The present invention further provides a process for the preparation and purification of eslicarbazepine acetate.
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Page/Page column 22; 23
(2013/03/26)
-
- PROCESS FOR THE PREPARATION OF OXCARBAZEPINE
-
The present invention relates to an improved process for the preparation of 10-oxo-10,11-dihydiO-5H-dibenz[b,fjazepine-5-carboxamide (Oxcarbazepine) by reacting 10-methoxy-5H-dibenz[b,f]azepine (10-methoxyiminostilbene) and alkali metal cyanate in presence of α-hydroxy acids, and also relates to the process for the preparation of carbamazepine from iminostilbene. Further the present invention is directed to the novel crystalline form of 10-methoxy carbamazepine.
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Page/Page column 4
(2011/04/18)
-
- Methods for predicting the response to statins
-
The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.
- -
-
-
- METHOD FOR CHEMICAL SYNTHESIS OF OXCARBAZEPINE
-
Method for chemical synthesis of oxcarbazepine comprises adding 5-cyano-10-nitro-5H-dibenz[b,f]azepine of formula III, Raney nickel catalyst, and organic solvent into a reactor, adding hydrogen at 2-20A, controlling the temperature to 40-120°C and carrying out reduction reaction, filtering after reacting completely, hydrolyzing the filtrate by adding 20-36.5 mass% hydrochloric acid, concentrating and cooling crystallizing the reaction solution, and obtaining the oxcarbazepion. The method has advantages of advanced process, simple and safe operation, and high product purity and yield, which is suitable for commercial production.
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-
Page/Page column 4
(2011/05/04)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF OXCARBAZEPINE
-
The present invention relates to an improved process for the preparation of 10-oxo- 10,l l-dihydiO-5H-dibenz[b,fjazepine-5-carboxamide (Oxcarbazepine) by reacting 10-methoxy-5H-dibenz[b,f]azepine (10-methoxyiminostilbene) and alkali metal cyanate in presence of α-hydroxy acids, and also relates to the process for the preparation of carbamazepine from iminostilbene. Further the present invention is directed to the novel crystalline form of 10-methoxy carbamazepine.
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Page/Page column 10
(2009/12/23)
-
- Process for the Preparation of 10,11-Dihydro-10-Oxo-5H-Dibenz[B,F] Azepine-5-Carboxamide
-
A process for preparing 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, compound of formula (I), said process comprising a. reacting compound of formula (Ivb) with alkali metal methoxide to yield compound of formula (II); and b. converting compound of formula (II) to compound of formula (I).
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Page/Page column 4
(2008/12/04)
-
- PROCESS FOR PRODUCING 10-OXO-L10, 11-DIHYDR0-5H-DIBENZ [B, F] AZEPINE-5-CARBOXAMIDE STARTING FROM 5-CYANOIMINOSTILBENE
-
Disclosed herein is a process for producing 10-oxo-10,11-dihydro-5H-dibenz[bf] azepine-5-carboxamide of formula I via novel intermediates 11-alkoxy-10-halo-10,11-dihydro-5H-dibenzo [b,f ] azepine-5-carbonitrile [XIX] or 10-alkoxy-5H-dibenz [b,f] azepine -5-carbonitrile [XX]. Further the present invention also provides a process for preparation of said intermediates.
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-
Page/Page column 14
(2008/06/13)
-
- PROCESS FOR PRODUCING OXCARBAZEPINE VIA AN 11-ALKOXY-10-HALO-DIHYDROIMINOSTILBENE INTERMEDIATE
-
Disclosed herein is an economically viable and cost effective process for preparation of oxcarbazepine of formula (I) via a novel intermediate of formula (XVIII).
- -
-
Page/Page column 14-15
(2010/11/29)
-
- Process for the preparation of oxcarbazepine
-
The reaction between 10-methoxy-iminostilbene (IV) and of(trichloromethyl)carbonate affords 10-methoxy-N-chlorocarbonyliminostilbene (XVI) in high yields, then ammonolysis and subsequent hydrolysis of the enol ether provides particularly pure oxcarbazepine.
- -
-
Page/Page column 8
(2008/06/13)
-
- A new industrial process for oxcarbazepine
-
A novel industrial process for the antiepileptic drug oxcarbazepine 1 has been developed. Unlike the old process, the new process is free from halogenated solvents and can be performed in standard production equipment. It starts from commercially available 1,3-dihydro-1-phenyl-2H-indol-2-one 10. In the key step, an electrophilic ring closure reaction of 2-[(methoxycarbonyl)phenylamino] benzeneacetic acid 5 to 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxylic acid methyl ester 6 in poly phosphoric acid was applied. For the manufacture of 5, a highly efficient process using a dianion strategy was developed.
- Fuenfschilling, Peter C.,Zaugg, Werner,Beutler, Ulrich,Kaufmann, Daniel,Lohse, Olivier,Mutz, Jean-Paul,Onken, Ulrich,Reber, Jean-Louis,Shenton, David
-
p. 272 - 277
(2012/12/24)
-
- Process for the preparation of carboxamide compounds
-
A process for preparing 5H-dibenz[b,f]azepine-5-carboxamide of the general formula: wherein R1, R2, R3 and R4 are the same or different and can be hydrogen, halogen, nitro, cyano, carboxyl, R, —CO(R), —OCO(R), —O(R), —N(R)2, —CON(R)2, and —COO(R), wherein R is selected from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C5-C10 cycloalkenyl, C2-C10 alkynyl, and C6-C20 aryl, wherein the two A groups of —N(A)2 and —CON(A)2 can be the same or different, and wherein R2 and R3 can together form a bond is provided; the process comprising reacting 5H-dibenz[b,f]azepine of the general formula wherein R1, R2, R3 and R4 have the aforementioned meanings, with one or more alkali or alkaline-earth cyanates and in the presence of one or more unsaturated dicarboxylic acids.
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-
Page/Page column 5-6
(2008/06/13)
-
- 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
-
Novel process for preparation of 10-oxo-10, 11-dihydro-SH-dibenz[b,f] azepine-5--carboxamide (oxcarbazepine) via intermediate 10-methoxy-5H--dibenz [b,f] azepine -5 carbonyl, chloride; comprising the steps: a) Preparation of an intermediate 10-methoxy-5H-dibenz [b,f] azepine -5 carbonyl, chloride from 10-methoxyiminostillbene using bis (trichloromethyl) carbonate (BTC) with organic base such as aliphatic or aromatic tertiary amines in organic solvent b) Conversion of the intermediate to 10-methoxy-5H-dlbenz[b,f] azepine -5-- carboxamide using ammonia in organic solvent c) Formation of oxcarbazepine from step(b) using Lewis acid in an organic solvent at a temperature between 25°C - 80°C, preferably at 50°C to 70°C d) Isolation of oxcarbazepine.
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Page/Page column 8
(2008/06/13)
-
- PROCESS FOR PREPARING OXCARBAZEPINE
-
Process for preparing oxcarbazepine according to Scheme 1: characterized by the use of triphosgene as chlorocarbonylating agent in step a).
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-
Page/Page column 6;7
(2008/06/13)
-
- An advantageous route to oxcarbazepine (Trileptal) based on palladium-catalyzed arylations free of transmetallating agents
-
(Chemical Equation Presented) A new route to oxcarbazepine (Trileptal), the most widely prescribed antiepileptic drug, starting from commercially available 2′-aminoacetophenone and 1,2-dibromobenzene, is reported. The sequentially accomplished key steps are palladium-catalyzed intermolecular α-arylation of ketone enolates and intramolecular N-arylation reactions. After several experiments to establish the best conditions for both arylation processes, the target oxcarbazepine is obtained in a satisfactory overall yield, minimizing the number of steps and employing scalable catalytic procedures developed in partially aqueous media.
- Carril, Monica,SanMartin, Raul,Churruca, Fatima,Tellitu, Imanol,Dominguez, Esther
-
p. 4787 - 4789
(2007/10/03)
-
- USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
-
The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
- -
-
-
- Process for the preparation of oxcarbazepine and related intermediates
-
A process for preparing Oxcarbazepine III comprising: a) reacting oximinostilbene IV with chlorosulfonyl isocyanate in an inert organic solvent and isolating compound V b) hydrolyzing compound V to form crude Oxcarbazepine III c) purifying oxcarbazepine.
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Page/Page column 3
(2008/06/13)
-
- A new synthesis of oxcarbazepine using a Friedel-Crafts cyclization strategy
-
A novel, simple, and straightforward process for the large-scale synthesis of oxcarbazepine, the active ingredient of Trileptal, a medicine for the treatment of epilepsy, has been developed. Starting from readily available 1,3-dihydro-1-phenyl-2H-indol-2-one, a Friedel-Crafts cyclization strategy provides a direct route to the tricyclic framework of the target molecule. Crucial to the success of the strategy was the choice of the proper nitrogen-protecting group.
- Kaufmann, Daniel,Fünfschilling, Peter C.,Beutler, Ulrich,Hoehn, Pascale,Lohse, Olivier,Zaugg, Werner
-
p. 5275 - 5278
(2007/10/03)
-
- Low temperature, high conversion, liquid-phase benzylic oxidation with dioxygen by metal/NHPI-catalyzed co-oxidation with benzaldehyde
-
A new liquid-phase catalytic oxidation system for the low temperature, high conversion benzylic mono-oxyfunctionalization of 10,11-dihydrocarbamazepine (1) into oxcarbazepine (4) with dioxygen has been developed. The method is based on a co-oxidation of 1 with benzaldehyde in the presence of a four-component catalyst system consisting of Co(OAc)2, Ni(OAc)2, Cr(NO3)3, and N-hydroxyphthalimide (NHPI). The influence of the catalyst system on the formation and decomposition of the crucial hydroperoxide intermediate 2 has been investigated. Based on these results, the role of each of the components in the catalyst system is discussed. The scope of this method for the oxidation of other substrates has been studied, and the results are compared with those obtained by Co/NHPI catalyzed oxidation of these substrates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- De Vondervoort, Lizette Schmieder-van,Bouttemy, Sabine,Heu, Ferdinand,Weissenboeck, Kurt,Alsters, Paul L.
-
p. 578 - 586
(2007/10/03)
-
- METHOD OF PREPARING A 5H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE
-
The present invention provides a method of preparing a 5H-dibenz[b,f]azepine-5-carboxamide of formula (1) wherein R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, carboxyl, A, -CO(A), -OCO(A), -O(A), -N(A)2, -CON(A)2, and -COO(A), wherein A is selected from the group consisting of C-1-C10 alkyl, C3-C10 cycloalkyl, C-2-C10 alkenyl, C-5-C10 cycloalkenyl, C-2-C10 alkynyl, and C-6-C20 aryl, wherein the two A groups of -N(A)2 and -CON(A)2 can be the same or different, and wherein R2 and R3 can together form a bond; comprising reacting a 5H-dibenz[b,f]azepine of formula (2) with a) a cyanate salt selected from the group consisting of alkali metal cyanate salts and alkaline-earth metal cyanate salts, and b) a salt of an amino compound having no N-H bonds, wherein the salt has a Ka (25° C) of at least about 10 x 10-11.
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-
-
- Process for the preparation of 10-methoxycarbamazepine
-
A process for the preparation of 10-methoxycarbamazepine, an important intermediate in the preparation of 10-oxo-10, 11-dihydro-5H-dibenz(b,f)azepine-5-carboxamide(oxcarbazepine) from 10-methoxy-5H-dibenz(b,f)azepine(10-methoxyiminostilbene), is disclosed, which process comprises reacting 10-methoxyiminostilbene with cyanic acid (HOCN) in the presence of a mild acidic reagent in a solvent. Also disclosed is an improved method for the hydrolysis of 10-methoxycarbamazepine to oxcarbazepine, which method comprises carrying out the hydrolysis in a biphasic system chosen such that the oxcarbazepine is substantially insoluble in both phases, whereas the by-products or impurities are soluble in at least one of the phases. The oxcarbazepine thereby prepared is an anticonvulsant, and has been proposed for use as an anti-epileptical agent in the treatment of AIDS-related neural disorders, and for the treatment of Parkinson's disease and/or Parkinsonian syndromes.
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-
-
- Dibenzo(b,f)azepine derivatives and their preparation
-
The invention relates to new processes for the preparation of the pharmaceutical oxcarbazepine, as well as novel intermediates prepared by or used for said processes, and the preparation of said intermediates.
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-
-
- Process for the oxidation of substrates containing methyl, methylene or methine groups
-
Process for the oxidation of substrates containing methyl, methylene or methine groups by cooxidation with an aldehyde as cosubstrate in the presence of a catalyst system consisting of an imide compound and a metal cocatalyst.
- -
-
-
- New synthesis of oxcarbazepine via remote metalation of protected N-o-tolyl-anthranilamide derivatives
-
Benzyl and allyl protected N-o-tolyl-anthranilamides were efficiently prepared by Buchwald-Hartwig C-N cross coupling reactions, followed by protection of the amino group. Under directed remote metalation conditions, protected dibenzoazepinones were obtained in good yields. Deprotection of the amine and conversion to an urea furnished a new and efficient synthesis of the antiepileptic drug Trileptal.
- Lohse, Olivier,Beutler, Ulrich,Fünfschilling, Peter,Furet, Pascal,France, Julien,Kaufmann, Daniel,Penn, Gerhard,Zaugg, Werner
-
p. 385 - 389
(2007/10/03)
-
- Process for the preparation of 10-OXO-10, 11-dihydro-5H-dibenz (b,f) azepin-5-carboxamide
-
A novel process for the preparation of 10-0×0-10,11-dihydro-5H-dibenz(b,f)azepin-5-carboxamide (VI) consists of starting group 10-methoxy-5H-dibenz(b,f)azepine (IV) and subjecting compound (IV) to direct carbamoylation with isocyanic acid generated in situ from cyanates and acids and then subjecting the product to acid hydrolysis of the enol ether. An alternative process to obtain (VI) starts (IV) effecting the hydrolysis reaction before the carbamoylation. In this case the carbamoylating agent is chlorosulfonyl isocyanate.
- -
-
-
- Teratogenicity of carbamazepine-10,11-epoxide and oxcarbazepine in the SWV mouse
-
The mechanism of carbamazepine (CBZ)-related teratogenicity was investigated in the SWV mouse by contrasting the effects of CBZ-10,11- epoxide (CBZE) and oxcarbazepine (OXC) treatments. Dietary CBZE administration was initiated 2 weeks before mating and continued through day 18 of gestation. OXC was administered to pregnant dams by garage on day 6 of gestation and continued through day 18 of gestation. Maternal plasma concentrations of CBZE ranged from 1.4 to 17.7 μg/ml and OXC ranged from 6.1 to 15.9 μg/ml. In comparison, clinical plasma concentrations of CBZE ranged from 1 to 2 μg/ml and OXC plasma concentrations were 1 μg/ml or less. The incidence of malformation were 14%, 27% and 26% after daily CBZE doses of 300, 600 and 1000 mg/kg, respectively, compared with a 6% incidence in no- drug control mice, P a 5% incidence in no-drug controls, P > .05. Phenobarbital cotreatment (45 mg/kg/day) with OXC (1100 mg/kg/day) did not lead to changes in the incidence of malformation when compared with OXC (1100 mg/kg/day) dosed alone. These data are consistent with a teratogenic CBZ metabolite, possibly CBZE, or with oxidation of CBZE or CBZ at positions on the aromatic ring leading to the formation of reactive intermediates such as arene oxides or quinones.
- Bennett, Greg D.,Amore, Benny M.,Finnell, Richard H.,Wlodarczyk,Kalhorn, Thomas F.,Skiles, Gary L.,Nelson, Sidney D.,Slattery, John T.
-
p. 1237 - 1242
(2007/10/03)
-
- Process for the manufacture of 5-carbamoyl-10-oxo-10,11-dihydro-5H-dibenz[b,]azepine
-
The invention relates to a process for the manufacture of the known 5-carbamoyl-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine of the formula III which is characterized in that, for example, 5-cyano-5H-dibenz[b,f]azepine of the formula I is nitrated to form 5-cyano-10-nitro-5H-dibenz[b,f]azepine of the formula II, this is subjected to hydrolysis, then reduction, then the reduction product contained in the reaction mixture is subjected to hydrolysis and the end product of the formula III is isolated in pure form. The process is illustrated by the following reaction scheme: STR1 The invention relates also to new intermediates produced in these reactions.
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