- Synthetic route of lacosamide
-
The invention discloses a new synthesis route of lacosamide. The new synthesis route comprises the following steps: taking glycine ethyl ester hydrochloride as an initial raw material to react with methylbenzene, benzophenone and p-toluenesulfonic acid to obtain a compound of formula M1; reacting the compound of formula M1 with Xmethyl methyl ether to generate a compound of formula M2; reacting the compound of formula M2 with benzylamine under the catalytic action of sodium ethoxide to generate a compound of formula M3; reacting the compound of formula M3 under the action of acid to generate acompound of formula M4; reacting the compound of formula M4 with Ltartaric acid to generate a compound of formula M5; and enabling the compound of formula M5 to react with acetic anhydride to generate the lacosamide compound. The synthesis route has the advantages that the atom economy is high, the use of isopropyl chloroformate highly toxic products for preparing amide is avoided, the use of methylation reagents methyl iodide or dimethyl sulfate is avoided, the yield is high, and the like.
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Paragraph 0022
(2021/03/31)
-
- Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives
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A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C?C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.
- Teloxa, Saul F.,Kennington, Stuart C. D.,Camats, Marc,Romea, Pedro,Urpí, Fèlix,Aullón, Gabriel,Font-Bardia, Mercè
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supporting information
p. 11540 - 11548
(2020/08/10)
-
- Enantioselective three-component Ugi reaction catalyzed by chiral phosphoric acid
-
A catalytic enantioselective three-component Ugi reaction was developed. SPINOL-derived phosphoric acid with bulky 2,4,6-tricyclohexylphenyl groups at the 6,6′ positions was found to be the best catalyst to afford α-amino amide derivatives in good to excellent yields (62% to 99%) and enantiocontrol (81% to >99% enantiomeric excess). This asymmetric reaction was applicable well to an array of aliphatic aldehydes. The gram-scale synthesis, modification of dapsone, and enantioselective synthesis of (R)-Lacosamide underline the general utility of this methodology Influence of dihedral angles and substituents of the chiral phosphoric acids on the enantioselectivity was also discussed in this article.
- Zhang, Jian,Wang, Yi-Yan,Sun, He,Li, Shao-Yu,Xiang, Shao-Hua,Tan, Bin
-
-
- Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts
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Amidation of unprotected amino acids has been investigated using a variety of ‘classical“ coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.
- Sabatini, Marco T.,Karaluka, Valerija,Lanigan, Rachel M.,Boulton, Lee T.,Badland, Matthew,Sheppard, Tom D.
-
supporting information
p. 7033 - 7043
(2018/05/04)
-
- Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-11C-Acetylation of Peptides
-
A mild and effective method is described for 11C-labeling of peptides selectively at the N-terminal nitrogen or at internal lysine positions. The presented method relies on the use of specific biphosphine palladium–methyl complexes and their high reactivity towards amino-carbonylation of amine groups in the presence [11C]carbon monoxide. The protocol facilitates the production of native N-11C-acetylated peptides, without any structural modifications and has been applied to a selection of bioactive peptides.
- Andersen, Thomas L.,Nordeman, Patrik,Christoffersen, Heidi F.,Audrain, Hélène,Antoni, Gunnar,Skrydstrup, Troels
-
supporting information
p. 4549 - 4553
(2017/04/13)
-
- Method for preparing lacosamide by microreactor
-
The invention discloses a method for preparing lacosamide by a microreactor. According to the method, D-serine is used as a starting raw material to take a condensation reaction with aniline for obtaining a compound I; then, methylation reaction is performed with a methylation reagent to obtain a compound II; then, acetylation reaction is performed with an acetylation reagent to obtain the lacosamide; the at least methylation reaction is performed in the microreactor. Compared with a conventional method, the method provided by the invention has the advantages that the protection is not needed on the amidogen of the D-serine; the synthesis route is reduced from the five-step reaction to the three-step reaction; the reaction steps are greatly simplified; meanwhile, the reaction conditions are mild; the safety is high; the environment-friendly effect is good; the byproducts in each step are few; the product yield is high; the method is suitable for industrial production. The formulas are shown as the accompanying drawing.
- -
-
Paragraph 0056; 0057; 0067
(2017/07/20)
-
- Improved preparation method of modified lacosamide
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The invention discloses an improved preparation method of modified lacosamide, which is simple to operate, high in chiral purity and low in cost. According to the improved preparation method, in step 1, amidation is carried out on amino by utilizing di-tert butyl dicarbonate (Boc for short), wherein conditions are moderate and the chiral purity is high and at least reaches 90 percent or more; in step 4, high-selectivity dimethyl sulfate is used as a methylation reagent; the cost is low and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application. The improved preparation method has the most important innovation points that the Boc is used as an N-protection agent and a Boc protecting group can be simply and conveniently removed by adding acid and a hydrogenation removal means does not need to be used. Secondly, the low-price dimethyl sulfate is used for carrying out methylation and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application.
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-
-
- Direct amidation of unprotected amino acids using B(OCH2CF3)3
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A commercially available borate ester, B(OCH2CF3)3, can be used to achieve protecting-group free direct amidation of α-amino acids with a range of amines in cyclopentyl methyl ether. The method can be applied to the synthesis of medicinally relevant compounds, and can be scaled up to obtain gram quantities of products.
- Lanigan, Rachel M.,Karaluka, Valerija,Sabatini, Marco T.,Starkov, Pavel,Badland, Matthew,Boulton, Lee,Sheppard, Tom D.
-
supporting information
p. 8846 - 8849
(2016/07/22)
-
- IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE AND ITS NOVEL INTERMEDIATE
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An improved, cost effective process for the preparation of Lacosamide is disclosed. A novel intermediate of formula (IV) and a process for preparation of the novel intermediate is also disclosed. wherein, X is halogen.
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Page/Page column 13
(2016/03/22)
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- Process for the preparation of(R)-Lacosamide
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The present invention is directed towards an improved, five step method for the preparation of the anti-epileptic drug (R)-Lacosamide, as illustrated in FIG. 2. The active form of the drug is (R)-enantiomer and the present method gives high yields of (R)-enantiomer of lacosamide. The method does not involve use of any unnatural amino acids as starting material or use of protection/deprotection strategies, strong acids or hydrogenation. Instead, the method uses a cheap and easily available racemic butadiene monoepoxide as the starting material.
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-
-
- 3-Azaspiro[5,5]undecan-2,4-dioxo-3-yl diphenyl phosphate (ASUD-diphenyl phosphate), a new reagent for the synthesis of the N-protected amino acid-ASUD ester
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A new reagent, 3-azaspiro[5,5]undecan-2,4-dioxo-3-yl diphenyl phosphate (ASUD-diphenyl phosphate) is described for the synthesis of N-protected amino acid-ASUD esters which are active esters useful in the synthesis of peptides. This compound was synthesized by reacting N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione (HO-ASUD) with diphenyl chlorophosphate in the presence of a base at room temperature and was obtained in high yields. The ASUD-diphenyl phosphate reagent reacts with N-protected amino acids under mild conditions to give the corresponding ASUD active esters, while preserving the enantiomeric purity of the amino acid. The new reagent is a stable crystalline compound and eliminates the need for DCC, a potent skin allergen, used previously for the synthesis of N-protected amino acid-ASUD ester.
- Rao, B. Leelamaheswara,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
-
p. 487 - 491
(2016/06/06)
-
- A rakow amide preparation method
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A preparing process of lacosamide is disclosed. D-serine is adopted as an initial raw material. The method includes: performing amino protection, performing methylation, condensing with benzylamine under a condition of existence of a carboxyl activator, removing an amino protection group, and performing amidation to obtain the lacosamide. The total yield is higher than 66%. The method is high in yield, simple and convenient to operate, high in product purity and especially suitable for industrial production.
- -
-
Paragraph 0121; 0122
(2016/10/17)
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- An enantioselective approach to functionalized amino acids: Total synthesis of antiepileptic drug (R)-lacosamide
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A short and highly efficient synthetic approach to enantiopure functionalized amino acids (FAAs) 1 skeleton from racemic butadiene monoepoxide as a starting material and its application to the total synthesis of an antiepileptic drug (R)-lacosamide 2 are described. The synthesis utilizes the palladium catalyzed Trosts Dynamic Kinetic Asymmetric Transformation (DYKAT) as key step.
- Garg, Yuvraj,Pandey, Satyendra Kumar
-
supporting information
p. 4201 - 4203
(2015/05/05)
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- PROCESS FOR THE PREPARATION OF LACOSAMIDE USING NOVEL INTERMEDIATES
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The present invention provides an improved and commercial process for the preparation of Lacosamide having formula (I). Further, the present invention also provides the novel intermediate compounds of formula (VI) and (VII) and their process for the preparation. Present process utilizes compound of formula (VI) and (VI)I as key novel intermediates for the preparation of Lacosamide.
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-
-
- NEW PROCESS
-
There is provided a process for the preparation of Lacosamide in a particular polymorphic form, which process involves the isolation of a salt of formula I : according to the methods defined in the application.
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Page/Page column 33
(2014/05/24)
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- LACOSAMIDE INTERMEDIATE COMPOUND, PREPARATION METHOD THEREOF AND USE THEREOF
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A new compound is provided, which is used for preparing lacosamide. A novel method for preparing lacosamide is also provided. During the reaction, iodomethane and silver oxide that are cost expensive are not used, nor a Pd-c catalyst is used, so the production cost is low, the raw materials and accessory materials are cheap and easily available, and the process is simple, so that industrial production is easy to realize; and moreover, the yield is high, and good economic efficiency can be achieved.
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-
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- PROCESS FOR THE PREPARATION OF LACOSAMIDE
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The present invention relates to an improved process for the preparation of Lacosamide of Formula (I), comprising: O-methylating a compound of Formula (V) or a compound of Formula (XX) or a compound of Formula XXII; in the presence of a methylating agent and a base to produce Lacosamide of Formula (I).
- -
-
Paragraph 0124
(2013/05/22)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
The present invention relates to an improved process for the preparation of Lacosamide having formula (I).
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-
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- PROCESS FOR THE PREPARATION OF LACOSAMIDE
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The present invention relates to a novel and improved process for the preparation of lacosamide, wherein the process is a sequential one-pot process.
- -
-
-
- LACOSAMIDE INTERMEDIATE COMPOUND, PREPARATION METHOD THEREOF AND USE THEREOF
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A new compound is provided, which is used for preparing lacosamide. A novel method for preparing lacosamide is also provided. During the reaction, iodomethane and silver oxide that are cost expensive are not used, nor a Pd-c catalyst is used, so the production cost is low, the raw materials and accessory materials are cheap and easily available, and the process is simple, so that industrial production is easy to realize; and moreover, the yield is high, and good economic efficiency can be achieved.
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Page/Page column 6
(2012/11/13)
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- PROCESS FOR PREPARATION OF LACOSAMIDE AND SOME N-BENZYL-PROPANAMIDE INTERMEDIATE DERIVATIVES
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The present invention discloses novel process for the preparation of (2R)-2-acetamido-N- benzyl-3-methoxypropanamide of Formula I involving novel intermediates of Formula - XIX and Formula - XX.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
The present invention relates to a novel and improved process for the preparation of lacosamide, wherein the process is a sequential one-pot process.
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- NOVEL POLYMORPH OF LACOSAMIDE
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The present invention provides novel crystalline form of lacosamide, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides a process for the preparation of lacosamide amorphous form.
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Page/Page column 10
(2012/04/23)
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- Primary amino acid derivatives: Compounds with anticonvulsant and neuropathic pain protection activities
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Pharmacological management remains the primary method to treat epilepsy and neuropathic pain. We have advanced a novel class of anticonvulsants termed functionalized amino acids (FAAs). In this study, we examine FAA derivatives from which the terminal acetyl moiety was removed and termed these compounds primary amino acid derivatives (PAADs). Twenty-seven PAADs were prepared; the central C(2) R-substituent was varied, including C(2) stereochemistry, and the compounds were tested in rodent models of seizures and neuropathic pain. C(2)-Hydrocarbon N-benzylamide PAADs were potent anticonvulsants and excellent anticonvulsant activity (mice, ip; rat, po) was observed for C(2) R-substituted PAADs in which the R group was ethyl, isopropyl, or tert-butyl, and the C(2) stereochemistry conformed to the d-amino acid configuration ((R)-stereoisomer). These values surpassed the activities of several clinical antiepileptic drugs. The C(2) (R)-ethyl and C(2) (R)-isopropyl PAADs also displayed excellent activities in the mouse (ip) formalin neuropathic pain model. Significantly, unlike the FAA structure-activity relationship, PAAD anticonvulsant activity increased upon substitution of a methylene unit for a heteroatom in the R-substituent that was one atom removed from the C(2) site, suggesting that these PAADs function by a different pathway than FAAs.
- King, Amber M.,Salomé, Christophe,Dinsmore, Jason,Salomé-Grosjean, Elise,De Ryck, Marc,Kaminski, Rafal,Valade, Anne,Kohn, Harold
-
supporting information; experimental part
p. 4815 - 4830
(2011/10/01)
-
- 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 40
(2011/09/15)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
The present invention relates to an improved process for the preparation of Lacosamide of Formula (I), comprising: O-methylating a compound of Formula (V) or a compound of Formula (XX) or a compound of Formula XXII; in the presence of a methylating agent and a base to produce Lacosamide of Formula (I).
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Page/Page column 30
(2011/12/04)
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- Intermediate for producing lacosamide and a process for its preparation and conversion to lacosamide
-
The invention relates to R)-1-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (compound III) with an ee of greater than 90%. and a process for producing the same
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-
-
- Intermediate for producing lacosamide and a process for its preparation and conversion to lacosamide
-
The invention relates to ((R)-1-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (compound III) with an ee of greater than 90%. and a process for producing the same.
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- PROCESSES FOR PREPARATION OF POLYMORPHIC FORMS OF LACOSAMIDE
-
The present invention relates to processes for the preparation of crystalline polymorphic forms of lacosamide (Formula I), including processes for inter-conversion among such polymorphic forms.
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Page/Page column 13-14
(2011/06/19)
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- PROCESSES FOR REDUCING IMPURITIES IN LACOSAMIDE
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The present invention relates to processes for reducing impurities in lacosamide during the preparation of lacosamide. The invention provides processes for minimizing or removing impurities such as (2R)-2-(acetylamino)-3-(benzylamino)-3-oxopropyl acetate of Formula II or (2R)-2-propanoylamino-N-benzyl-3-methoxypropionamide of Formula III in lacosamide.
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Page/Page column 14
(2011/08/21)
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- Solid Forms Of An N-(Phenylmethyl)Propanamide Derivative And Processes Of Preparation
-
The invention relates to solid forms of the anti-epileptic agent lacosamide (I). The invention also relates to mixtures of solid forms of lacosamide. The invention further relates to mixtures of lacosamide enantiomers crystallized in a conglomerate Form and the use thereof in providing enantiomerically enriched lacosamide, preferably lacosamide enriched with the (R)-enantiomer of lacosamide.
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Page/Page column 7
(2011/02/26)
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- PROCESS FOR PREPARING (R)-N-BENZYL-2-(BENYLOXYCARBONYLAMINO)-3-METHOXYPROPIONAMIDE
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(R)—N-benzyl-2-(benzyloxycarbonylamino)-3-methoxypropionamide is an intermediate useful for preparing lacosamide. It can be prepared, for example, by combining (R)—N-benzyl-2-(benzyloxycarbonylamino)-3-hydroxypropionamide with dimethylsulfate, followed by mixing with an alkali or alkaline earth metal hydroxide at a temperature of about 25° C. to about ?15° C.
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Page/Page column 6
(2010/10/03)
-
- Intermediate compounds and their use in preparation of lacosamide
-
The present invention is concerned with novel compounds and their use for the preparation of lacosamide. The present invention also contemplates processes for the preparation of lacosamide employing the novel compound of general Formula II, Formula IIa or Formula IIb as intermediate. Wherein R1 is -OH or -OMe; R2 is -OH or -NH-CH2-C6H5.
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Page/Page column 13
(2009/06/27)
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- INTERMEDIATE COMPOUNDS AND THEIR USE IN PREPARATION OF LACOSAMIDE
-
The present invention is concerned with novel compounds and their use for the preparation of lacosamide. The present invention also contemplates processes for the preparation of lacosamide employing the novel compound of general Formula II, Formula IIa or Formula IIb as intermediate. Wherein R1 is —OH or —OMe;R2 is —OH or —NH—CH2—C6H5.
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Page/Page column 7
(2009/06/27)
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- IMPROVED SYNTHESIS SCHEME FOR LACOSAMIDE
-
The present invention is concerned with an improved method of producing (R)-2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide) comprising the 0-methylation of a compound of formula (I) to produce a compound of formula (I I) in a single step reaction.
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Page/Page column 18-19
(2010/10/20)
-
- Design and evaluation of affinity labels of functionalized amino acid anticonvulsants
-
Studies have shown that functionalized amino acids (FAA) exhibit outstanding activity in the maximal electroshock-induced seizure (MES) test in rodents. Affinity labels patterned in part after the potent antiepileptic (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2) have been prepared as mechanistic probes to learn the pharmacological basis for FAA function. The chemical reactivity of the affinity labels with nucleophiles was assessed, and the labels were evaluated in in vitro radioligand assays and in the MES tests in rodents. The affinity labels did not bind to receptors known to effect seizure spread. Three affinity labels, (R,S)-N-benzyl-2-acetamido-6-isothiocyanatohexanamide ((R,S)-5), (R)-N-(4-isothiocyanatobenzyl)-2-acetamido-3-methoxypropionamide ((R)-6), and (R)-N-(3-isothiocyanatobenzyl)-2-acetamido-3-methoxy-propionamide ((R)-7), possessed excellent in vivo anticonvulsant activity and exhibited maximal activity at later time periods than typically observed for FAA. The anticonvulsant activity of 6 and 7 resided primarily in the (R)-enantiomer and the activity of (R)-6 and (R)-7 in rats (po) exceeded that of phenytoin. The chemical properties, pharmacological profile, and marked stereospecificity associated with 6 and 7 anticonvulsant activity make these compounds useful pharmacological tools for the study of the mode of action of FAA.
- LeTiran, Arnaud,Stables, James P.,Kohn, Harold
-
p. 4762 - 4773
(2007/10/03)
-
- Anticonvulsant enantiomeric amino acid derivatives
-
The present invention is directed to N-benzyl-2-amino-3-methoxypropionamide and stereoisomers the use thereof anti-convulsant and an intermediate in the preparation of other anti-convulsants.
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-
- Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives
-
Efficient procedures for the synthesis of (R)-N-benzyl-2-amino-3- methoxypropionamide ((R)-3), 2-acetamido-3-methoxypropionic acid (4), and O- methylserine (5) are described beginning from (R)-Cbz-serine ((R)-7). The reactions proceeded with little or no racemization and permitted the synthesis of the potent anticonvulsant (R)N-benzyl-2-acetamido-3- methoxypropionamide ((R)-2). The anticonvulsant activities of 2-4 were determined revealing the surprising activity of (R)-2.
- Andurkar, Shridhar V.,Stables, James P.,Kohn, Harold
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p. 3841 - 3854
(2007/10/03)
-