21616-46-6

Usage

InChI:InChI=1/C16H14N2O3/c19-11-18-14(20)16(17-15(18)21,12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,19H,11H2,(H,17,21)

Upstream product

• 50-00-0 formaldehyd 
• 57-41-0 phenythoin 
• 584-08-7 potassium carbonate 

Downstream Products

• 33588-93-1 3-bromomethyl-5,5-diphenyl-imidazolidine-2,4-dione 
• 123360-25-8 <(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methyl>-6-methylpyridine-3-carboxylate 
• 85901-32-2 Propionic acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester 
• 85901-34-4 3-pentanoyloxymethyl 5,5-diphenylhydantoin 
• 123337-31-5 <(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methyl>-3-bromopropionate 
• 85901-38-8 3-octanoyloxymethyl 5,5-diphenylhydantoin 
• 123337-30-4 <(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methyl>bromoacetate 
• 85901-39-9 Nonanoic acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester 
• 71919-14-7 3-(hydroxymethyl)-5,5-diphenylhydantoin N,N-dimethylglycine ester 
• 123337-33-7 <(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methyl>-4-bromobutyrate 
• 123337-34-8 <(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methyl>-3-bromo-2-methylpropionate 
• 150994-96-0 rac-1-(2,3-O-Isopropylidene glycerol)-3-<(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methoxycarbonyl>propionic acid ester 
• 150995-00-9 2-Phenyl-1,3-dioxane-5-yl-<(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methoxy>carbonic acid ester 
• 150994-94-8 2-(1,3-Benzylidene glycerol)-3-<(2,4-dioxo-5,5-diphenyl-3-imidazolidinyl)methoxycarbonyl>propionic acid ester 

Relevant academic research and scientific papers

Identification, synthesis, characterization and quality control strategy of new process-related impurities in fosphenytoin sodium

Fosphenytoin sodium is a water dissolvable phenytoin prodrug that is directed intravenously to convey phenytoin, conceivably more securely than intravenous phenytoin. It is most ordinarily utilized in the intense treatment of convulsive status epileptics. The examination of the procedure-related contaminants will not help exclusively to advance the process parameters yet additionally to create sensible analytical methods and set the quality standard for a quality control system in pharmaceutical manufacturing. During the production of fosphenytoin sodium, all the process-related impurities are controlled in every stage and three degradation impurities are managed in the final API as per USP monograph. Besides, five unknown and one known contaminants were detected by HPLC method. All these impurities were identified, synthesized, isolated and characterized by IR, 1D-NMR (1H, 13C, DEPT) and HRMS spectral techniques. The mechanism of the formed impurities is examined for the first time. Quality control procedures to manage these impurities were developed to acquire the mass medication of ICH grade quality.

Hydrolysis of pharmaceutically relevant phosphate monoester monoanions: Correlation to an established structure-reactivity relationship

The kinetics of dephosphorylation of dilute aqueous solutions of 3- phosphoryloxymethyl-5,5-diphenylhydantoin (1) and estrone phosphate (2) were studied as a function of pH, buffer concentration, and temperature at an ionic strength of 0.5 M. The resulting pH-rate profiles displayed bell- shaped regions with maxima between pH 3 and 5, where the monoanionic phosphate species predominate; mechanistically, these regions involved spontaneous or water-catalyzed dephosphorylation of the monoanionic phosphate species. The profile of 1 was also described with pathways involving a hydronium ion-catalyzed and a spontaneous or water-catalyzed dephosphorylation of the neutral species. The hydrolytic reactivities of the monoanionic species of the phosphomonoester prodrugs of phenytoin (i.e., 1), estrone (i.e., 2), and 2,2,2-trichloroethanol (from the literature) were well predicted by an established structure-reactivity, free-energy relationship. The correlation of these compounds to this relationship supported a common hydrolytic reaction mechanism. The small Bronsted value of -0.27 was consistent with a dephosphorylation mechanism involving a rapid transfer of the lone phosphoryl proton to the bridge-oxygen atom of the ester linkage, followed by the rate-limiting phosphorus-oxygen bond fission proceeding through a largely dissociative transition state.

Design, synthesis and biological evaluation of water-soluble phenytoin prodrugs considering the substrate recognition ability of human carboxylesterase 1

Human carboxylesterase 1 (hCES1) is a hydrolase that is mainly expressed in the liver and lung and plays the most important role in the metabolic activation of ester–type prodrugs. In this study, design, synthesis and evaluation of water–soluble phenytoin prodrugs were performed with consideration of the substrate recognition ability of hCES1. The phenytoin prodrugs were synthesized in two steps without column chromatography. It was confirmed that all prodrugs are efficiently converted to phenytoin in a human liver microsome (HLM) solution (up to 54.6 nmol/mg protein/min). Although some of the prodrugs were degraded in strongly basic solution, the solubility of all prodrugs was greater than that of phenytoin in buffer solutions at pH 7.4 and 8.3. Among the synthesized phenytoin prodrugs, the 3,3-dimethylglutarate prodrug was superior in terms of solubility and stability, and it showed solubility of 10 mg/mL or more (phenytoin: 0.1 mg/mL) in a solution of pH 8.3. It was also found that the 3,3-dimethylglutarate prodrug was selectively activated by hCES1 but not hCES2 or arylacetamidodeacetylase.

MANUFACTURING METHOD OF SODIUM FOSPHENYTOIN HYDRATE AND SYNTHETIC INTERMEDIATE THEREOF

PROBLEM TO BE SOLVED: To provide a manufacturing method of sodium fosphenytoin hydrate capable of shortening time for all manufacturing processes and reducing manufacturing cost and a synthetic intermediate thereof. SOLUTION: There is provided a method for manufacturing 3-hydroxymethyl-5,5-diphenyl-2,4-imidazolidinedione, including a process for heating 5,5-diphenyl-2,4-imidazolidinedione (phenytoin), formaldehyde and alcohol and using no alkaline material. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

Organic amine salt of fosphenytoin stability and its preparation and use

The invention relates to a stable organic amine salt of fosphenytoin and the preparation method and use thereof, the related organic amine salt of fosphenytoin having a structure of the general formula as shown in general formula (I), and the use comprisi

An oral redox-sensitive self-immolating prodrug strategy

We report a novel oral prodrug approach where a solubilizing polymer conjugated to the drug is designed to be released by the action of an exogenously administered agent in the intestine. A redox-sensitive self-immolating design was implemented, and the reconversion kinetics were studied for three reducible prodrugs.

Structure-activity relationships of 3-substituted-5,5-diphenylhydantoins as potential antiproliferative and antimicrobial agents

A series of twelve 3-substituted-5,5-diphenylhydantoins was synthesized, including some whose anticonvulsant activities have already been reported in the literature. Their antiproliferative activities against HCT-116 human colon carcinoma cells were evalu

Novel synthesis of fosphenytoin: Anti-convulsant prodrug

A simple, new synthesis of fosphenytoin sodium 1, a prodrug, via imidate ester and employing mild reaction conditions is described. Copyright Taylor & Francis Group, LLC.

Solvent effects on the structure-activity relationship of pharmacological active 3-substituted-5,5-diphenylhydantoins

Absorption spectra of eight 3-substituted-5,5-diphenylhydantoins have been recorded in fourteen solvents in the range 200-400 nm. The effect of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions are analyzed by means of the

PROCESS FOR PREPARING FOSPHENYTOIN

Processes for preparing fosphenytoin.