2999-46-4

Usage

Preparation

synthesis of ethyl isocyanoacetate A solution containing N-formyl glycine ethyl ester (1, 1.31 g, 10 mmol), DIPEA (2.62 g, 20 mmol) and DMAP (0.45 g, 3 mmol) in dry DCM (10 mL) was loaded in a sample loop and combined with a second stream containing triphosgene (2, 0.98 g, 3.3 mmol) also dissolved in dry DCM (10 mL) at individual channel flow rates of 0.5 mL/min. The combined stream was directed into two linked 10 mL FEP reactor vessels to achieve a 20 minutes residence time at ambient temperature. The output was collect and the solvent was carefully evaporated to 80% of its total volume. The crude material was filtered through silica (5 g) and washed with DCM (2 × 10 mL) to obtain the salt-free product. The desired product 3 was obtained as dark yellow oil after evaporation of the organic phase (1.03 g, 91 % isolated yield, >97% purity by 1H NMR).

InChI:InChI=1/C5H7NO2/c1-3-4(6-2)5(7)8/h4H,3H2,1H3,(H,7,8)/p-1

Upstream product

• 3154-51-6 ethyl N-formylglycinate 
• 593-75-9 methyl isocyanate 
• 105-58-8 Diethyl carbonate 
• 58948-98-4 potassium 2-isocyanoacetate 
• 56-40-6 glycine 
• 459-73-4 GlyOEt*HCl 
• 2491-15-8 formylglycine 
• 623-33-6 glycine ethyl ester hydrochloride 
• 109-94-4 formic acid ethyl ester 

Downstream Products

• 61323-28-2 ethyl-5‐phenyl‐1,3‐thiazole‐4‐carboxylate 
• 5602-94-8 N-carbomethoxyglycine ethyl ester 
• 32998-96-2 ethyl 5-benzyloxazole-4-carboxylate 
• 38062-11-2 4-Cyano-2-methyleneamino-3-phenyl-butyric acid ethyl ester 
• 25315-41-7 α-Formylamino-β-phenyl-zimtsaeure-ethylester 
• 62640-98-6 5-(D_r-1c_F,2t_F,3c_F,5-tetrakis-benzyloxy-4r_F-hydroxy-pent-cat_F-yl)-oxazole-4-carboxylic acid ethyl ester 
• 66107-90-2 5-(D_r-1c_F,2t_F,3c_F,5-tetrakis-benzyloxy-4r_F-hydroxy-pent-cat_F-yl)-oxazole-4-carboxylic acid benzyl ester 
• 61323-26-0 5-methyl-thiazole-4-carboxylic acid ethyl ester 
• 7298-97-7 β-Ethyl-DL-asparaginsaeure 
• 14527-43-6 ethyl thiazole-4-carboxylate 
• 30320-34-4 α-Isocyan-β-phenyl-glutarsaeure-diethylester 
• 32968-45-9 ethyl 5-ethyl-1,3-oxazole-4-carboxylate 
• 25315-40-6 ethyl N^α-formyl-α-cyclohexylideneglycinate 
• 136986-59-9 (Z)-2-Formylamino-3-(4-methoxy-phenyl)-acrylic acid ethyl ester 

Relevant academic research and scientific papers

Dispirooxindoles based on 2-selenoxo-imidazolidin-4-ones: Synthesis, cytotoxicity and ros generation ability

A regio-and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoim-idazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3′′-indoline]-2′′, 5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3′′-indoline]-2′′,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC50) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2– 6.9 and compound 6e—against the MCF7 cancer cell line (CC50 20.6 μM, HEK293T/A549 selectivity index 1.6); some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action.

Silver-Catalyzed Acyl Nitrene Transfer Reactions Involving Dioxazolones: Direct Assembly of N-Acylureas

Dioxazolones and isocyanides are useful synthetic building blocks, and have attracted significant attention from researchers. However, the silver-catalyzed nitrene transfer reaction of dioxazolones has not been investigated to date. Herein, a silver-catalyzed acyl nitrene transfer reaction involving dioxazolones, isocyanides, and water was realized in the presence of Ag2O to afford a series of N-acylureas in moderate to good yields.

ANTIVIRAL 1,3-DI-OXO-INDENE COMPOUNDS

The invention provides compounds of Formula (I): as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections.

Isocyanide 2.0

The isocyanide functionality due to its dichotomy between carbenoid and triple bond characters, with a nucleophilic and electrophilic terminal carbon, exhibits unusual reactivity in organic chemistry exemplified for example in the Ugi reaction. Unfortunately, the over proportional use of only a few isocyanides hampers novel discoveries about the fascinating reactivity of this functional group. The synthesis of a broad range of isocyanides with multiple functional groups is lengthy, inefficient, and exposes the chemist to hazardous fumes. Here we present an innovative isocyanide synthesis overcoming these problems by avoiding the aqueous workup which we exemplify by parallel synthesis from a 0.2 mmol scale performed in 96-well microtiter plates up to a 0.5 mol multigram scale. The advantages of our methodology include an increased synthesis speed, very mild conditions giving access to hitherto unknown or highly reactive classes of isocyanides, rapid access to large numbers of functionalized isocyanides, increased yields, high purity, proven scalability over 5 orders of magnitude, increased safety and less reaction waste resulting in a highly reduced environmental footprint. For example, the hitherto believed to be unstable 2-isocyanopyrimidine, 2-acylphenylisocyanides and even o-isocyanobenzaldehyde could be accessed on a preparative scale and their chemistry was explored. Our new isocyanide synthesis will enable easy access to uncharted isocyanide space and will result in many discoveries about the unusual reactivity of this functional group. This journal is

Influence of the C-terminal substituent on the crystal-state conformation of Adm peptides

The bis-functionalized diamondoid α-amino acid 2-aminoadamantane-2-carboxylic acid (Adm) has been used as the building block of four Nα-formyl homo-dipeptide alkylamide sequences via a solution-phase Ugi multicomponent reaction approach. The conformers of these peptides have been determined in the crystalline state by X-ray diffraction to distinguish the influences of the C-terminal substituent. One of the Adm peptides folds into an open and a hydrogen-bonded γ-turn geometry. Moreover, 3D-structures have been observed featuring two consecutive γ-turns in an incipient γ-helical structure, a significantly distorted nonhelical β-turn, as well as an S-shaped conformation with opposite helical screw senses. A significant topological variety is thus exhibited by the -Adm-Adm- sequences contingent on their C-terminal substituents, illustrating both the broad conformational potential and the need for further characterization of this sterically bulky residue in explorations of its ?, ψ space.

Copper-Catalyzed [3+2] Cycloaddition Reactions of Isocyanoacetates with Phosphaalkynes to Prepare 1,3-Azaphospholes

A novel copper-catalyzed synthetic method is described for phosphorous- and nitrogen-containing heterocycles such as 1,3-azaphospholes. Cycloaddition reactions of various isocyanoacetates with phosphaalkynes in the presence of copper bromide, bis(diphenylphosphino)methane (dppm), and potassium carbonate afford the corresponding 1,3-azaphospholes in high yields with complete selectivity. Some dppm-bridged dicopper complexes were identified as active species for the formation of 1,3-azaphospholes.

Strategies to develop selective CB2 receptor agonists from indole carboxamide synthetic cannabinoids

Activation of the CB2 receptor is an attractive therapeutic strategy for the treatment of a wide range of inflammatory diseases. However, receptor subtype selectivity is necessary in order to circumvent the psychoactive effects associated with activation of the CB1 receptor. We aimed to use potent, non-selective synthetic cannabinoids designer drugs to develop selective CB2 receptor agonists. Simple structural modifications such as moving the amide substituent of 3-amidoalkylindole synthetic cannabinoids to the 2-position and bioisosteric replacement of the indole core to the 7-azaindole scaffold are shown to be effective and general strategies to impart receptor subtype selectivity. 2-Amidoalkylindole 16 (EC50 CB1 > 10 μM, EC50 CB2 = 189 nM) and 3-amidoalkyl-7-azaindole 21 (EC50 CB1 > 10 μM, EC50 = 49 nM) were found to be potent and selective agonists with favourable physicochemical properties. Docking studies were used to elucidate the molecular basis for the observed receptor subtype selectivity for these compounds.

Silver-catalyzed [3+2+1] annulation of aryl amidines with benzyl isocyanide

A silver-catalyzed [3+2+1] annulation of amidines with benzyl isocyanide toward 2,4-diaryl-1,3,5-triazines was developed. A variety of symmetrical and unsymmetrical products were obtained in moderate to good yields. This work also features an oxidant-free approach to 2,4-disubstituted triazines.

One-step synthesis of N, N′-substituted 4-imidazolidinones by an isocyanide-based pseudo-five-multicomponent reaction

A pseudo-five-multicomponent reaction involving an isocyanide, a primary amine, two molecules of formaldehyde and water is reported, which gives N,N′-substituted 4-imidazolidinones when trifluoroethanol is used as the solvent. The reaction proceeds with good yields and with a wide variety of amines and isocyanides, providing an efficient new entry to these heterocycles. A preliminary study of the reaction mechanism suggests that trifluoroethanol, although acting as the solvent, is directly involved as a reagent in the reaction pathway.

PROCESSES FOR THE PREPARATION OF DIASTEREOMERICALLY AND ENANTIOMERICALLY ENRICHED OXAZOLINES

The invention relates to an industrially viable and advantageous process for the preparation of (2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, having the following formula (I) generally known as Droxidopa, or of intermediates useful in the synthesis thereof.