196601-69-1Relevant academic research and scientific papers
Synthetic route of lacosamide
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Paragraph 0022, (2021/03/31)
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.
Enantioselective three-component Ugi reaction catalyzed by chiral phosphoric acid
Zhang, Jian,Wang, Yi-Yan,Sun, He,Li, Shao-Yu,Xiang, Shao-Hua,Tan, Bin
, p. 47 - 54 (2019/11/11)
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.
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
Teloxa, Saul F.,Kennington, Stuart C. D.,Camats, Marc,Romea, Pedro,Urpí, Fèlix,Aullón, Gabriel,Font-Bardia, Mercè
supporting information, p. 11540 - 11548 (2020/08/10)
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.
Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts
Sabatini, Marco T.,Karaluka, Valerija,Lanigan, Rachel M.,Boulton, Lee T.,Badland, Matthew,Sheppard, Tom D.
supporting information, p. 7033 - 7043 (2018/05/04)
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.
Improved preparation method of modified lacosamide
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Paragraph 0036; 0051-0053, (2017/08/31)
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.
Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-11C-Acetylation of Peptides
Andersen, Thomas L.,Nordeman, Patrik,Christoffersen, Heidi F.,Audrain, Hélène,Antoni, Gunnar,Skrydstrup, Troels
supporting information, p. 4549 - 4553 (2017/04/13)
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.
Method for preparing lacosamide by microreactor
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Paragraph 0056; 0057; 0067, (2017/07/20)
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.
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
Rao, B. Leelamaheswara,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
, p. 487 - 491 (2016/06/06)
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.
A rakow amide preparation method
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Paragraph 0121; 0122, (2016/10/17)
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.
IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE AND ITS NOVEL INTERMEDIATE
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Page/Page column 13, (2016/03/22)
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.
