- Synthesis of S-licarbazepine by asymmetric reduction of oxcarbazepine with Saccharomyces cerevisiae CGMCC No. 2266
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S-licarbazepine was synthesized by asymmetric reduction of oxcarbazepine with CGMCC No. 2266. The optimum batch reduction conditions were found to consist of a reaction time of 36 h, temperature of 30 °C, and initial pH value of 7.0. The optimum concentration of the glucose co-substrate was found to be 0.3 mol L-1. The addition of glucose contributed to in situ regeneration of NADPH in cells and improved conversion. Conversion increased with the addition of more biomass and with a decrease in the initial concentration of substrate. Within the membrane reactor, a continuous reduction process was used to improve production efficiency and reduce the inhibition of high-concentration substrate upon reduction. The optimum flux was found to be 20 ml h-1. S-licarbazepine yield was 3.7678 mmol L-1 d -1 in continuous reduction over four days. The enantiometric excess of S-licarbazepine was 100% for both batch and continuous reduction processes.
- Ou, Zhi-Min,Shi, Han-Bing,Sun, Xing-Yuan,Shen, Wen-He
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Read Online
- Development of a practical, biocatalytic reduction for the manufacture of (s)-licarbazepine using an evolved ketoreductase
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This contribution describes the development of a ketoreductase enzyme over four rounds of directed evolution and the associated process development that enabled a practical, scalable process to (S)-licarbazepine (eslicarbazepine).
- Modukuru, Naga K.,Sukumaran, Joly,Collier, Steven J.,Chan, Ann Shu,Gohel, Anupam,Huisman, Gjalt W.,Keledjian, Raquel,Narayanaswamy, Karthik,Novick, Scott J.,Palanivel,Smith, Derek,Wei, Zhang,Wong, Brian,Yeo, Wan Lin,Entwistle, David A.
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Read Online
- Preparation method of eslicarbazepine
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The invention relates to the field of preparation of chemical substances and medicines, in particular to a preparation method of eslicarbazepine. The method is characterized in that oxcarbazepine is subjected to a reaction in the presence of a chiral catalyst and a hydrogen source to obtain eslicarbazepine, and the reaction equation is disclosed in the invention, wherein the chiral catalyst can be R1, R2, R3, R4, R5 and R6 which can be hydrogen or methyl respectively; M is Ru, Rh or Ir.
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Paragraph 0036-0050
(2021/04/21)
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- An industrial perspective fermentative bioreduction of aromatic ketones by Penicillium rubens VIT SS1 and Penicillium citrinum VIT SS2
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Microbial mediated, especially the fungi mediated asymmetric reduction of the ketone is one of the most promising tools for the synthesis of chiral alcohols. Many fungal cultures were isolated from soil and screened for the stereo selective bioreduction of acetophenone. The potential isolates are characterised using molecular techniques and found to be Penicillium rubens VIT SS1 (Genbank ID: MK063869) and Penicillium citrinum VIT SS2 (Genbank ID: MW960208). Both the isolates were tested for the bioreduction of few aromatic ketones such as 4-fluoro acetophenone, 3-hydroxy acetophenone, and oxcarbazepine, which are the key chiral intermediates of various pharmaceutical drugs. The P. rubens VIT SS1 produced (S)-alcohol obeying Prelog’s rule, and P. citrinum was anti-Prelog configuration in nature. Preparatory scale reactions were conducted using the optimised bioreduction process, and the keto loading was significantly increased by 12-fold (from 0.5 to 6 g/L) with >99% conversion and >98% enantiomeric excess. The study discloses the vast prospective approach of exploring filamentous fungi for sustainable synthesis of chiral alcohols in an environment-friendly, novel, and cost competent way.
- Jothi, Saravanan,Vuppu, Suneetha
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- Chiral amino-pyridine-phosphine tridentate ligand, manganese complex, and preparation method and application thereof
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The invention discloses a chiral amino-pyridine-phosphine tridentate ligand, a manganese complex, and a preparation method and application thereof. The chiral amino-pyridine-phosphine tridentate ligand is shown as a formula II, and the manganese complex of the chiral amino-pyridine-phosphine tridentate ligand can be used for efficiently catalyzing and hydrogenating ketone compounds to prepare chiral alcohol compounds in a high enantioselectivity mode. The chiral amino-pyridine-phosphine tridentate ligand and the manganese complex are simple in synthesis process, good in stability, high in catalytic activity and mild in reaction conditions.
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Paragraph 0597-0600; 0605
(2020/07/13)
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- Lutidine-Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones
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A series of MnI complexes containing lutidine-based chiral pincer ligands with modular and tunable structures has been developed. The complex shows unprecedentedly high activities (up to 9800 TON; TON=turnover number), broad substrate scope (81 examples), good functional-group tolerance, and excellent enantioselectivities (85–98 % ee) in the hydrogenation of various ketones. These aspects are rare in earth-abundant metal catalyzed hydrogenations. The utility of the protocol have been demonstrated in the asymmetric synthesis of a variety of key intermediates for chiral drugs. Preliminary mechanistic investigations indicate that an outer-sphere mode of substrate–catalyst interactions probably dominates the catalysis.
- Zhang, Linli,Tang, Yitian,Han, Zhaobin,Ding, Kuiling
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supporting information
p. 4973 - 4977
(2019/03/17)
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- Brain-targeting eslicarbazepine ester prodrug and application thereof
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The invention relates to an eslicarbazepine ester prodrug and an application thereof, wherein the prodrug is a compound represented by the formula (I) or optical isomers or physiologically acceptable salts of the compound represented by the formula (I), wherein R represents a lipophilic substituent. The compound represented by the formula (I) is the eslicarbazepine ester prodrug containing the lipophilic substituent, is converted into eslicarbazepine through metabolism in vivo to play pharmacological effects, and can be applied in preparation of drugs for treatment, prevention or adjuvant treatment of central nervous system diseases, such as epilepsy and the like.
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Paragraph 0132
(2017/08/28)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
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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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- One-step lipase-catalysed preparation of eslicarbazepine
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The antiepileptic eslicarbazepine (S-licarbazepine) has been prepared in one step from its racemic form RS-licarbazepine via lipase catalysed kinetic resolution. A novel stereoselective simultaneous HPLC separations of RS-licarbazepine (1) and its racemic esters RS-2-5 have been developed on Lux cellulose-2 column using cyclohexane/ethanol 1/1 v/v as mobile phase. The developed enantioselective HPLC separations have been utilized for monitoring of lipase catalyzed kinetic resolution of RS-licarbazepine (1). Lipase catalysed trans-esterification and hydrolysis reactions have been performed. Four different esters (acetate (2), propionate (3), butyrate (4) and benzoate (5)) have been investigated for both trans-esterification and hydrolysis using ten lipases from versatile origins. The best enantioselectivity was shown by trans-esterification of RS-licarbazepine with vinyl benzoate in MtBE as solvent and lipase from Candida rugosa where the pharmacologically active enantiomer, S-(+)-licarbazepine, has been accomplished [E = 31, ee = 97%, yield 84%, α20D = +105, c 0.001 g mL-1, CH3OH]. Molecular docking attributed the high enantioselectivity of the transesterification when using Candida rugosa lipase to unfavorable ligand contacts between the S-enantiomer and phenylalanine 296.
- El-Behairy,Sundby
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p. 98730 - 98736
(2016/11/06)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF EPILEPSY AND NEUROLOGICAL DISORDERS
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The invention relates to the compounds of formula I and formula Ia or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of formula I or formula Ia; and methods for treating or preventing epilepsy, seizures and convulsions 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, seizures and convulsions.
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Paragraph 0167; 0168; 0171; 0172
(2016/04/26)
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- IMPROVED PROCESS FOR THE PREPARATION OF ESLICARBAZEPINE AND ESLICARBAZEPINE ACETATE
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Object of the present invention is an improved process for the preparation of Elsicarbazepine and Eslicarbazepine acetate by means of chiral Ruthenium catalysts.
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Paragraph 00181-00182
(2016/09/26)
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- PROCESS FOR THE PREPARATION AND PURIFICATION OF ESLICARBAZEPINE ACETATE AND INTERMEDIATES THEREOF
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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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Paragraph 0075
(2015/03/16)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
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The invention relates to the compounds of formula (I) and formula (1A) 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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- Analysis of oxcarbazepine and the 10-hydroxycarbazepine enantiomers in plasma by LC-MS/MS: Application in a pharmacokinetic study
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Oxcarbazepine is a second-generation antiepileptic drug indicated as monotherapy or adjunctive therapy in the treatment of partial seizures or generalized tonic-clonic seizures in adults and children. It undergoes rapid presystemic reduction with formation of the active metabolite 10-hydroxycarbazepine (MHD), which has a chiral center at position 10, with the enantiomers (S)-(+)- and R-(-)-MHD showing similar antiepileptic effects. This study presents the development and validation of a method of sequential analysis of oxcarbazepine and MHD enantiomers in plasma using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Aliquots of 100 μL of plasma were extracted with a mixture of methyl tert-butyl ether: dichloromethane (2:1). The separation of oxcarbazepine and the MHD enantiomers was obtained on a chiral phase Chiralcel OD-H column, using a mixture of hexane:ethanol:isopropanol (80:15:5, v/v/v) as mobile phase at a flow rate of 1.3 mL/min with a split ratio of 1:5, and quantification was performed by LC-MS/MS. The limit of quantification was 12.5 ng oxcarbazepine and 31.25 ng of each MHD enantiomer/mL of plasma. The method was applied in the study of kinetic disposition of oxcarbazepine and the MHD enantiomers in the steady state after oral administration of 300 mg/12 h oxcarbazepine in a healthy volunteer. The maximum plasma concentration of oxcarbazepine was 1.2 μg/mL at 0.75 h. The kinetic disposition of MHD is enantioselective, with a higher proportion of the S-(+)-MHD enantiomer compared to R-(-)-MHD and an AUC0-12 S-(+)/R-(-) ratio of 5.44. Chirality 25:897-903, 2013. 2013 Wiley Periodicals, Inc.
- De Jesus Antunes, Natalicia,Wichert-Ana, Lauro,Coelho, Eduardo Barbosa,Della Pasqua, Oscar,Alexandre Jr., Veriano,Takayanagui, Osvaldo Massaiti,Tozatto, Eduardo,Lanchote, Vera Lucia
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p. 897 - 903
(2014/01/06)
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- PROCESS FOR THE PREPARATION AND PURIFICATION OF ESLICARBAZEPINE ACETATE AND INTERMEDIATES THEREOF
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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 13
(2013/03/26)
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- PROCESS FOR THE PREPARATION OF (S)-(+)- OR (R)-(-)-10-HYDROXY DIHYDRODIBENZ[B,F]AZEPINES BY ENANTIOSELECTIVE REDUCTION OF 10,11-DIHYDRO-10-OXO-5H-DIBENZ[B,F]AZEPINES AND POLYMORPHS THEREOF
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The present invention provides a novel process for the preparation of substituted optically pure (S)-(+)- or (R)-(?)-10-hydroxy-dihydrodibenz[b,f]azepines or derivatives thereof, starting from 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepines using boronate esters or their derivatives. The present invention also provides use of thus prepared (S)-(+)- or (R)-(?)-10-hydroxy-dihydrodibenz[b,f]azepines for the preparation of their ester such as (S)-(?)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide or (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide. The present invention also provides novel solid state crystalline forms J1, J2, J3, J4 and amorphous form of eslicarbazepine and the process for the preparation thereof. Also, the present invention provides novel solid state crystalline form and amorphous form of eslicarbazepine acetate and the process for the preparation thereof. The novel solid state forms of eslicarbazepine are useful for the preparation of derivatives of eslicarbazepine such as eslicarbazepine acetate.
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Paragraph 0166
(2014/02/15)
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- PROCESS FOR THE PREPARATION OF (S)-(+)-OR (R)-(-)-10 HYDROXY DIHYDRODIBENZ[B,F]AZEPINES BY ENANTIOSELECTIVE REDUCTION OF 10, 11-DIHYDRO-10-OXO-5H-DIBENZ[B,F]AZEPINES AND POLYMORPHS THEREOF
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The present invention provides a novel process for the preparation of substituted optically pure (S)-(+)- or (R)-(-)-10-hydroxy-dihydrodibenz[b,f]azepines or derivatives thereof, starting from 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepines using boronate esters or their derivatives. The present invention also provides use of thus prepared (S)-(+)- or (R)-(-)- 10-hydroxy-dihydrodibenz[b,f]azepines for the preparation of their ester such as (S)-(-)- 10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, or (R)-(+)-10-acetoxy- 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide. The present invention also provides novel solid state crystalline forms J1, J2, J3, J4 and amorphous form of eslicarbazepine and the process for the preparation thereof. Also, the present invention provides novel solid state crystalline form and amorphous form of eslicarbazepine acetate and the process for the preparation thereof. The novel solid state forms of eslicarbazepine are useful for the preparation of derivatives of eslicarbazepine such as eslicarbazepine acetate.
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Page/Page column 26-27
(2012/09/22)
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- PROCESS FOR THE RESOLUTION OF RACEMIC (±)-10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE
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A process for resolving racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide comprising reacting (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide with S-ibuprofen or a pharmaceutically acceptable salt thereof to form a mixture of the SS and SR diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, followed by separating the SS-ibuprofen ester from the SR ibuprofen ester, and removal of the S-ibuprofen moiety to form S-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide with a chiral purity greater than 90%.
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Page/Page column 16-17
(2012/09/22)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF (S)-10-ACETOXY-10,11-DIHYDRO-5H-DIBENZ[b,f]AZEPINE-5-CARBOXAMIDE
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The present invention relates to a process for the preparation of (S)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound of formula (1).
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Page/Page column 23
(2011/11/30)
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- PROCESS FOR PREPARATION OF ENANTIOMERS OF LICARBAZEPINE
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The present invention provides a process for the preparation of eslicarbazepine and rlicarbazepine and their acetates by resolution of racemic licarbazepine using acetyl mandelic acid.
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Page/Page column 10
(2011/10/13)
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- ESLICARBAZEPINE ACETATE AND ITS POLYMORPHS
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Processes for the preparation of eslicarbazepine acetate and intermediates thereof. Also provided are polymorphic forms of eslicarbazepine acetate and methods for their preparation.
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Page/Page column 40
(2011/08/08)
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- PROCESS FOR PREPARING (S)-(-)-10-ACETOXY-10,11-DIHYDRO-5H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE AND ITS ESTERS THEREOF
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Disclosed herein an enzymatic process for preparing (S)-(-)-10-acetoxy-10,11- 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 eslicarbazepine.
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- PROCESS FOR THE ASYMMETRIC TRANSFER HYDROGENATION OF KETONES
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The invention relates to a process for the asymmetric transfer hydrogenation of a ketone substrate to produce as chiral secondary alcohol with an ee of greater than 85% in which an enantio-enriched chiral catalyst containing ruthenium or rhodium is used with a hydrogen donor and in which an anion exchange resin is used as a base.
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Page/Page column 10
(2011/11/06)
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- Process for the asymmetric hydrogenation of ketones
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The invention relates to a process for the asymmetric transfer hydrogenation of a ketone substrate to produce as chiral secondary alcohol with an ee of greater than 85% in which an enantio-enriched chiral catalyst containing ruthenium or rhodium is used with a hydrogen donor and in which an anion exchange resin is used as a base.
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Page/Page column 6
(2011/11/12)
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- A PROCESS FOR THE PURIFICATION OF ESLICARBAZEPINE ACETATE
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The present invention relates to the purification and particle size of eslicarbazepine acetate. The present invention also relates to the physical characteristics of solid state eslicarbazepine acetate, and pharmaceutical compositions containing the same.
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Page/Page column 14
(2010/11/03)
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- ASYMMETRIC CATALYTIC REDUCTION OF OXCARBAZEPINE
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A process for preparing (S)-(+)- 10,11 -dihydro-10-hydroxy-5H- dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,l l-dihydro-10-hydroxy-5H- dibenz/b,f/azepine-5-carboxamide, by reduction of oxcarbazepine in the presence of a catalyst and a hydride source is disclosed. The catalyst is prepared from a combination of [RuX2 (L)]2 wherein X is chlorine, bromine or iodine, and L is an aryl or aryl-aliphatic ligand, with a ligand of formula (A) or formula (B): wherein R1 is chosen from C1-6 alkoxy and C1-6 alkyl, n is a number from 0 to 5, and when n is a number from 2 to 5, R1 can be the same or different, and R2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl. The hydride source is either NR3R4R5 and formic acid, [R3R4R5NH][OOCH] and optionally formic acid, or [M][OOCH]x and formic acid, wherein R3, R4 and R5 are C1-6 alkyl, M is an alkali metal or alkaline earth metal and x is 1 or 2. A pH from 6.5 to 8 is maintained during the process.
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Page/Page column 17-18
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF (S)-(+)-10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ (B,F) AZEPINE-5-CARBOXYAMIDE
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(S)-(+)-10,11-Dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxyamide is prepared starting from racemic 5-cyano-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine by phthaloylation, separation of the diastereomeric salts of the phthaloyl derivative with (S)-phenylethylamine, hydrolysis of the (S, S) salt to (S)-(+)-5-cyano-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine and hydrolysis of the nitrile group of the latter to amido group, by treatment with peroxy compounds in alkali medium.
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Page/Page column 3; 4; 6
(2008/06/13)
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- Use of s-10-hydroxy-10,11-dihydro-carbamazepine for the treatment of anxiety and bipolar disorders
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The present invention relates to the use of a racemate of the compound of formula (1) consisting of at least 85% S-enantiomer and not more than 15% R-enantiomer or of pharmaceutically acceptable salts of said racemate or of the S-enantiomer of formula I or of pharmaceutically acceptable salts of said enantiomer for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies or for the treatment of affective and attention disorders; pharmaceutical compositions for that purpose and packages comprising said pharmaceutical compositions together with instructions for the use of said compositions for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies or of affective and attention disorders.
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Page/Page column 3
(2008/06/13)
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- DISINTEGRATING TABLETS COMPRISING LICARBAZEPINE
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The invention relates to pharmaceutical compositions comprising 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (also referred to as “licarbazepine”) as drug substance.
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Page/Page column 13-14
(2008/06/13)
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- ORAL MATRIX FORMULATIONS COMPRISING LICARBAZEPINE
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The invention relates to pharmaceutical compositions comprising 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (also referred to as "licarbazepine") as drug substance.
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Page/Page column 16
(2008/06/13)
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- Enantioselective process for the preparation of both enantiomers of 10,11-dihydro-10-hydroxy-5Hdibenz[b,f]azepine-5-carboxamide and new crystal forms thereof
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The invention relates to a novel process for the manufacture of substituted enantiopure 10hydroxy--dihydrodibenz[b,f]azepines (la), (lb) wherein each of R1and R2, independently, are hydrogen, halogen, amino or nitro; and each of R3 and R4, independently, are hydrogen or C1-C6alkyl; by transfer hydrogenation of 10-oxo-dihydrodibenz[b,f]azepines; and to novel catalysts of formula (III'a) and (III'b) wherein M is Ru, Rh, Ir, Fe, Co or Ni; L1 is hydrogen; L2 represents an aryl or aryl-aliphatic residue; and the further radicals have the meanings as defined herein; and to new crystal forms of both enantiomers of 10,11-dihydro-10 hydroxy-5Hdibenz[b,f]azepine-5-carboxamide, obtainable by the new processes, their usage in the production of pharmaceutical preparations, new pharmaceutical preparations comprising these new crystal forms and/or the use of these new crystal forms in the treatment of disorders such as epilepsy, or in the production of pharmaceutical formulations which are suitable for this treatment.
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- Anticonvulsant and sodium channel-blocking properties of novel 10,11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives
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A series of esters of the major metabolite of oxcarbazepine (2), 10,11- dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)- 12 were the most active of the series against MES-induced seizures with oral ED50 values at t(max) of 10.9 ± 2.3 and 4.7 ± 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 and 10, 6 and 12, and 7 and 11) were found to differ in the MES or rotarod tests; the ED50 value for (S)-6 against MES- induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage- sensitive sodium channels was studied by investigating [3H]-batrachotoxinin A 20-α-benzoate ([3H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [3H]BTX to sodium channels and the influx of 22Na+ into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.
- Benes, Jan,Parada, António,Figueiredo, Anabela A.,Alves, Paula C.,Freitas, Ana P.,Learmonth, David A.,Cunha, Rodrigo A.,Garrett, José,Soares-Da-Silva, Patrício
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p. 2582 - 2587
(2007/10/03)
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