86-34-0

Usage

Uses

Used in Neurological Applications:
Phensuximide is used as an anticonvulsant drug for the treatment of neurological disorders stemming from the brain, specifically targeting petit mal seizures. It helps in managing epilepsy and reducing the frequency and severity of seizures.
Used in Epilepsy Treatment:
Phensuximide, similar to ethosuximide, is used as an anticonvulsant drug in minor forms of epilepsy. It plays a crucial role in controlling seizures and improving the quality of life for patients suffering from this condition.

Originator

Milontin, Parke Davis, US ,1953

Manufacturing Process

10 grams of phenylsuccinic anhydride is dissolved in 250 ml of absolute ether and the solution is treated with dry methylamine until a precipitate ceases to form. After standing for ? hour the ether is decanted off and the residue iswashed with 40 ml of water by decantation. The mixture is filtered and the precipitate washed with 10 ml of water. By acidification of the filtrate, a white precipitate is obtained. After drying it weighs 8 grams and melts at 136°140°C. The two precipitates are combined and recrystallized from aqueous alcohol to give β-N-methylphenylsuccinamic acid which melts at 158°-160°C.9 grams of β-N-methylphenylsuccinamic acid and 200 ml of acetyl chloride are heated together on a steam bath for ? hour. The excess acetyl chloride is removed by distillation and 50 ml of water are added to the thick residue. After allowing for hydrolysis of the excess acetyl chloride the water is decanted and the yellow residue dissolved in 75 ml of ether. The resulting solution is treated with charcoal twice and dried over anhydrous magnesium sulfate. On partial evaporation of the ether a white solid precipitates. There is obtained 4 grams of N-methyl-α-phenylsuccinimide which melts at 71°-73°C.

Therapeutic Function

Anticonvulsant

Clinical Use

Phensuximide occasionally is used for the treatment of absence seizures refractory to other drugs, although it is considered to be less effective than ethosuximide. It is excreted in both urine and bile, and it may cause harmless pink to red discoloration of the urine. It should be used with caution in patients with acute intermittent porphyria.

Synthesis

Phensuximide, 1-methyl-3-phenylpyrrolidine-2,5-dione (9.3.5) is synthesized by the reaction of phenylsuccinic acid or its anhydride with methylamine [10,11].

Purification Methods

Crystallise phensuximide from hot 95% EtOH (m 72-73o). At 25o 1g of the imide dissolves in 1g of *C6H6, 18g of Et2O, 9.5g of EtOH, 5.1g of MeOH and 235g of H2O. [Beilstein 21 II 300, 21 III/IV 5465.]

InChI:InChI=1S/C11H11NO2/c1-12-10(13)7-9(11(12)14)8-5-3-2-4-6-8/h2-6,9H,7H2,1H3

Upstream product

• 54433-49-7 1-methyl- 3-phenyl-1H-pyrrole-2,5-dione 
• 635-51-8 2-phenylsuccinic acid 
• 74-89-5 methylamine 
• 1131-15-3 2-phenylsuccinic anhydride 
• 398130-26-2 1-methyl-3-methylsulfanyl-4-phenyl-pyrrole-2,5-dione 
• 853955-69-8 [2-(hydroxymethyl)phenyl]dimethyl(phenyl)silane 
• 930-88-1 N-methylmaleimide 
• 22903-00-0 3-(methylthio)-4-phenyl-1H-pyrrole-2,5-dione 
• 49601-28-7 5-hydroxyimino-4-methylthio-3-phenyl-3-pyrrolin-2-one 
• 140-29-4 phenylacetonitrile 
• 36122-35-7 2-phenylmaleic anhydride 
• 6837-05-4 (+/-)-2-phenyl-1,4-butanediol 
• 62-53-3 aniline 
• 65-85-0 benzoic acid 

Downstream Products

• 54433-49-7 1-methyl- 3-phenyl-1H-pyrrole-2,5-dione 
• 97233-04-0 (S)-1-methyl-3-phenylpyrrolidine-2,5-dione 
• 19509-06-9 1-methyl-3-phenylpyrrolidine 
• 13217-97-5 1-methyl-3-phenyl-1H-pyrrole 

Relevant academic research and scientific papers

Aminoketyl Radicals in Organic Synthesis: Stereoselective Cyclization of Five- and Six-Membered Cyclic Imides to 2-Azabicycles Using SmI2-H2O

Synthetic application of aminoketyl radicals [R-C?(O-)NR′R″] formed by a direct electron capture into the amide bond is limited. Herein, we demonstrate addition of aminoketyl radicals to unactivated alkenes using SmI2-H2O as a crucial promoter based on the generic five- and six-membered imide template. Notably, this method enables direct access to aminoketyl radicals with wide-ranging applications in synthesis for the formation of C-C bonds adjacent to nitrogen via polarity reversal.

General access to C-centered radicals: Combining a bioinspired photocatalyst with boronic acids in aqueous media

Carbon-centered radicals are indispensable building blocks for modern synthetic chemistry. In recent years, visible light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies, deuterium labeling, radical-trapping experiments, and spectroscopic analysis.

A Unified Strategy for the Synthesis of Difluoromethyl- And Vinylfluoride-Containing Scaffolds

Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical, scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl group, this approach provides a valuable tool for late-stage functionalization and drug development.

Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase

A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.

Mild Decarboxylative C?H Alkylation: Computational Insights for Solvent-Robust Ruthenium(II) Domino Manifold

Computational studies on decarboxylative C?H alkenylations provided key insights into the solvent-robust nature of C?H activation/decarboxylation domino reactions. These properties were exploited for ruthenium(II)-catalyzed C?H alkylations by a decarboxylative process with ample scope under copper-free and silver-free reaction conditions.

Highly Enantioselective Synthesis of Chiral Succinimides via Rh/Bisphosphine-Thiourea-Catalyzed Asymmetric Hydrogenation

We have successfully developed a highly enantioselective hydrogenation of various 3-aryl and 3-methyl maleinimides to access enantiomerically pure 3-substituted succinimides catalyzed by Rh/bisphosphine-thiourea (ZhaoPhos). This efficient catalytic system furnished the desired 3-substituted succinimide products with high yields and enantioselectivities (up to 99% yield, full conversions, almost all 3-aryl succinimide products up to 99% ee, and 3-methyl succinimide with 83% ee). Our catalytic system has a strong substrate tolerance and generality. Whether the N-substituted group of maleinimides is H or other protecting groups, the maleinimides were hydrogenated well (up to >99% ee, 99% yield). Moreover, the hydrogenation succinimide products can be readily utilized for the construction of biologically active molecules, such as chiral amides and pyrrolidines.

Pd(II)/bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated amides

The Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acid to α,β-unsaturated amides was developed and optimized, and the reaction was proceeded smoothly in air. A series of arylboronic acid and α,β-unsaturated amide substrates were surveyed, and modest to excellent yields were given.

Selective and tunable synthesis of 3-arylsuccinimides and 3-arylmaleimides from arenediazonium tetrafluoroborates and maleimides

A highly efficient synthetic strategy for synthesizing 3-arylsuccinimides has been developed from arenediazonium tetrafluoroborates and maleimides in the presence of TiCl3. The reactions generated 3-arylsuccinimides in satisfactory yields under mild reaction conditions. In addition, 3-arylmaleimides were obtained by the coupling of arenediazonium tetrafluoroborate and maleimides catalyzed by CuCl. This methodology provided the selective and tunable synthesis of two classes of products by simply switching different metal reagents. The methods are simple, efficient and practical.

Direct Synthesis of Chiral 3-Arylsuccinimides by Rhodium-Catalyzed Enantioselective Conjugate Addition of Arylboronic Acids to Maleimides

Chiral rhodium catalysts comprising 2,5-diaryl- substituted bicyclo[2.2.1]diene ligands L1-L10 were utilized in the enantioselective 1,4-addition reaction of arylboronic acids to N-substituted maleimides. In the presence of 2.5mol % of RhI/L2, enantioenriched conjugate addition adducts were isolated in 72-99 % yields with 86-98 %ee. This protocol offers a convenient method to access a variety of 3-arylsuccinimides in a highly enantioselective manner. Maleimides with readily cleavable N-protecting groups were tolerated enabling the synthesis of useful synthetic intermediates. Pyrrolidine 4, a biologically active compound, and pyrrolidine 5, an ent-precursor to an HSD-1 inhibitor, were synthesized to demonstrate the utility of this method. The road to rhodium! Enantioselective conjugate addition of a range of arylboronic acids to variously N-substituted maleimides, catalyzed by RhI complexes prepared in situ using chiral bicyclo[2.2.1]diene ligands, afforded the corresponding 3-arylsuccinimides with up to 98 %ee at 50 C (see scheme).

Versatile and sustainable synthesis of cyclic imides from dicarboxylic acids and amines by Nb2O5 as a base-tolerant heterogeneous lewis acid catalyst

Catalytic condensation of dicarboxylics acid and amines without excess amount of activating reagents is the most atom-efficient but unprecedented synthetic method of cyclic imides. Here we present the first general catalytic method, proceeding selectively and efficiently in the presence of a commercial Nb2O5 as a reusable and base-tolerant heterogeneous Lewis acid catalyst. The method is effective for the direct synthesis of pharmaceutically or industrially important cyclic imides, such as phensuximide, N-hydroxyphthalimide (NHPI), and unsubstituted cyclic imides from dicarboxylic acid or anhydrides with amines, hydroxylamine, or ammonia.