- Method for preparing Lacosamide by one-pot method
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The invention discloses a method for preparing Lacosamide by a one-pot method. The method comprises the steps: subjecting D-serine and an acetylation reagent to a reaction in a manner of taking dichloromethane as a solvent, and adjusting the pH of a reacted substance to 12-13 by an organic base after the reaction ends; then, controlling the temperature to -5 to 0 DEG C, and adding methyl trifluoromethanesulfonate into the reacted substance for a reaction; and cooling a reacted substance to the temperature of -30 to -25 DEG C, adding a dehydrating agent and benzylamine into the reacted substance for a reaction, carrying out depressurized-concentration drying on material liquid after the reaction ends so as to obtain crude Lacosamide, and then, carrying out recrystallization, thereby obtaining pure Lacosamide. The preparation method is simple and easy in operation, and the prepared Lacosamide has the purity of 99.90% or more and the chiral purity of 99.90%.
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Paragraph 0039
(2016/12/16)
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- METHOD FOR PREPARING LACOSAMIDE
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The present invention provides a novel method for preparing lacosamide with high chiral purity from D-serine. The method of the present invention can obtain lacosamide with high chiral purity in a high yield through a simple and environmentally-friendly process and thus can be easily applied to mass production.
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Paragraph 0030; 0031
(2016/12/01)
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- A Method for preparing Lacosamide
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In the present invention, provided is a novel method of manufacturing lacosamide with high purity of chiral from D-serine, which is allowed to obtain lacosamide with high purity of chiral in high yield through a simple, eco-friendly process and is accordingly used in mass-production.COPYRIGHT KIPO 2015
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Paragraph 0030; 0034-0036
(2016/12/07)
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- Substituted N -(biphenyl-4′-yl)methyl (R)-2-acetamido-3- methoxypropionamides: Potent anticonvulsants that affect frequency (Use) dependence and slow inactivation of sodium channels
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We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.
- Lee, Hyosung,Park, Ki Duk,Torregrosa, Robert,Yang, Xiao-Fang,Dustrude, Erik T.,Wang, Yuying,Wilson, Sarah M.,Barbosa, Cindy,Xiao, Yucheng,Cummins, Theodore R.,Khanna, Rajesh,Kohn, Harold
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p. 6165 - 6182
(2014/08/18)
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- PROCESS FOR PREPARING (R)-2-ACETAMIDO-N-BENZYL-3-METHOXY-PROPIONAMIDE
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Processes for preparing and purifying (R)-2-acetamido-N-benzyl-3-methoxy- propionamide of formula-1 and intermediates thereof are provided.
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Page/Page column 33-34
(2011/09/15)
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- PREPARATION OF LACOSAMIDE
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Processes for preparing lacosamide, for use in pharmaceutical compositions comprising lacosamide.
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Page/Page column 22
(2011/11/01)
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- Synthesis and anticonvulsant activities of (R)-N-(4′-substituted) benzyl 2-acetamido-3-methoxypropionamides
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The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide [(R)-N-benzyl 2-acetamido-3- methoxypropionamide, (R)-3] has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2′, 3′, 4′) showed that 4′-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4′-site. The SAR indicated that nonbulky 4′-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were comparable with or exceeded that of (R)-3 and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate. 2009 American Chemical Society.
- Salomé, Christophe,Salomé-Grosjean, Elise,Park, Ki Duk,Morieux, Pierre,Swendiman, Robert,DeMarco, Erica,Stables, James P.,Kohn, Harold
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supporting information; experimental part
p. 1288 - 1305
(2010/07/10)
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- Development of a high throughput screening tool for biotransformations utilising a thermophilic l-aminoacylase enzyme
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Micro-reactors containing a monolith-immobilised thermophilic l-aminoacylase, from Thermococcus litoralis, have been developed for use in biotransformation reactions and a study has been carried out to investigate the stereospecificity and stability of the immobilised enzyme. The potential to use the developed micro-reactors as a tool for rapid screening of enzyme specificity was demonstrated, confirming that the l-aminoacylase showed a similar substrate specificity to that previously reported of the free enzyme. From this baseline, the technique was employed as a tool to evaluate potential unreported substrates with N-benzoyl- (l-threonine, l-leucine and l-arginine) and N-acetyl- (d,l-serine, d,l-leucine, l-tyrosine and l-lysine) protecting groups. The order of preferred substrates was found to be Phe > Thr > Leu > Arg for N-benzoyl substrates and Phe ? Ser > Leu > Met > Tyr > Trp for N-acetyl substrates. It was found that by using the micro-reactor a significantly smaller quantity of enzyme and substrates was required. It was shown that the micro-reactors were still operational in the presence of selected organic solvents, such as ethanol, methanol, acetone, dimethylformamide (DMF) and dimethylsulfoxide (DMSO). The results indicated that a combination of a small amount of an appropriate solvent (5% DMSO) and a higher reaction temperature could be employed in biotransformations where substrate solubility was an issue.
- Ngamsom,Hickey,Greenway,Littlechild,Watts,Wiles
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scheme or table
p. 81 - 86
(2010/10/21)
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- NOVEL N-BENZYLAMIDE SUBSTITUTED DERIVATIVES OF 2-(ACYLAMIDO)ACETIC ACID AND 2-(ACYLAMIDO)PROPIONIC ACIDS: POTENT NEUROLOGICAL AGENTS
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A first aspect of the invention is a compound (sometimes also referred to herein as an "active agent" or "active compound") of Formula (I) or ( Ia): or a pharmaceutically acceptable salt or prodrug thereof. Compositions thereof and methods of using the same (e.g. for the treatment of a neurological disease) are also described.
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Page/Page column 50-51
(2009/12/27)
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- Microwave-assisted ring expansion of N-acetyl 3′-unsubstituted aziridine in the presence of Lewis acids
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The microwave-assisted ring expansion of N-acetyl 3′-unsubstituted aziridine-2-imides and N-acetyl 3′-unsubstituted aziridine-2-esters to oxazolines is reported. The regioselectivities of the rearrangements depend upon the reaction conditions, such as the Lewis acid selected and the solvent.
- Cardillo,Gentilucci,Gianotti,Tolomelli
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p. 2807 - 2812
(2007/10/03)
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- Ring expansion of N-acetyl aziridine-2-imides to oxazoline-4-imides, useful precursors of pure β-hydroxy α-aminoacids
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Optically active N-acyl aziridine 2-imides or α-carboxylates rearrange to oxazoline-4-imides or 4-carboxylates with high regio and stereo control. This ring expansion followed by mild hydrolisis allows the synthesis of enantiomerically pure β-hydroxy α-aminoacid precursors.
- Cardillo, Giuliana,Gentilucci, Luca,Tolomelli, Alessandra,Tomasini, Claudia
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p. 6953 - 6956
(2007/10/03)
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- Synthesis and anticonvulsant activities of N-benzyl-2-acetamidopropionamide derivatives
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Studies have demonstrated that 2-substituted N-benzyl-2-acetamidoacetamides (2) are potent anticonvulsants. A recent investigation has led to the hypothesis that an important structural feature in 2 for maximal anticonvulsant activity is the placement of a small, substituted heteroatom moiety one atom from the C(2) site. This paper validates this hypothesis. Twelve derivatives of N-benzyl-2-acetamidopropionamide have been prepared in which six different heteroatom substituents (chloro, bromo, iodo, oxygen, nitrogen, and sulfur) were incorporated at the C(3) site. Highly potent activities were observed for the two oxygen-substituted derivatives, N-benzyl-2-acetamido-3-methoxypropionamide (18) and N-benzyl-2-acetamido-3-ethoxypropionamide (19). The ED50 values in mice following intraperitoneal (ip) dosing for the maximal electroschock-induced seizure test for 18 and 19 were 8.3 and 17.3 mg/kg, respectively. These values compared favorably to the ED50 value found for phenytoin (ED50 = 6.5 mg/kg). Comparable activities were observed for 18 and 19 upon oral (po) administration to rats (18, ED50 = 3.9 mg/kg; 19, ED50 = 19 mg/kg; phenytoin, ED50 = 23 mg/kg). Evaluation of the individual stereoisomers for 18 demonstrated that the principal anticonvulsant activity resided in the (R)-stereoisomer. The ED50 value for (R)-18 was 4.5 mg/kg, and the ED50 for (S)-18 exceeded 100 mg/kg. This difference in activity for the two stereochemical isomers surpassed comparable values for other members within this class of compounds. The protective indices (PI = TD50/ED50) (where TD50 represents a neurotoxic dose impairing rotorod performance) for (R)-18 in mice (ip) and in rats (po) were 6.0 and > 130, respectively.
- Choi, Daeock,Stables, James P.,Kohn, Harold
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p. 1907 - 1916
(2007/10/03)
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- Kinetic Resolution of Unnatural and Rarely Occuring Amino Acids: Enantioselective Hydrolysis of N-Acyl Amino Acids Catalyzed by Acylase I
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Acylase I (aminoacylase; N-acylamino-acid amidohydrolase, EC 3.5.1.14, from porcine kidney and the fungus Aspergillus) is broadly applicable enzymatic catalyst for the kinetic resolution of unnatural and rarely occuring α-amino acids.Its enantioselectivity for the hydrolysis of N-acyl L-α-amino acids is nearly absolute, yet it accepts substrates having a wide range of structure and functionality.This paper reports the initial rates of enzyme-catalyzed hydrolysis of over 50 N-acyl amino acids and analogues, the stabilities of the enzymes in aqueous and aqueous/organic solutions, and the effects of different acyl groups and metal ions on the rates of enzymatic hydrolysis.Eleven α-amino and α-methyl α-amino acids were resolved on a 2-29-g scale.Crude L- and D-amino acid products had generally >90percent ee.The utility of resolved amino acids as chiral synthons was illustrated by the preparation of (R)- and (S)-1-butene oxide and the diastereoselective (cis:trans, 7-8:1) iodolactonization of three 2-amino-4-alkenoic acid derivatives.
- Chenault, H. Keith,Dahmer, Juergen,Whitesides, George M.
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p. 6354 - 6364
(2007/10/02)
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