cas 1198-97-6, 4-Phenyl-2-pyrrolidinone | Articles data

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Divergent Synthesis of γ-Amino Acid and γ-Lactam Derivatives from meso-Glutaric Anhydrides
The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation–cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.
Connon, Stephen J.,Craig, Ryan,Smith, Simon N.
p. 13378 - 13382
(2020)
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Substituted 1-methyl-4-phenylpyrrolidin-2-ones – Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors
N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue – 1-methyl-4-phenylpyrrolidin-2-one – and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.
Hilton-Proctor, J. P.,Ilyichova, O.,Jennings, I. G.,Johnstone, R. W.,Mountford, S. J.,Scanlon, M. J.,Shortt, J.,Thompson, P. E.,Zheng, Z.
(2020)
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Dendritic polyglycerol as a high-loading support for parallel multistep synthesis of GABA lactam analogues
A general route to 4-substituted azolidin-2-ones (GABA lactam analogues) on a soluble high-loading polyglycerol support has been developed and optimized. These biologically interesting compounds (anticonvulsive drugs) can be synthesized in three steps commencing from a polyglycerol supported (diethylphosphono)acetic acid and a carbonyl compound. The key features of this parallel approach are the cyclative cleavage and simple separation techniques (i.e., dialysis).
Roller, Sebastian,Siegers, Conrad,Haag, Rainer
p. 8711 - 8720
(2004)
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Synthesis and Biological Analysis of Anti-addiction Effect and Hepatotoxicity of Tow Baclofen Analogues Complexed with β-Cyclodextrin
Aim and Objective: The excessive consumption of alcohol and the installation of dependence is, in most cases, facilitated by favorable psychological factors that trigger and maintain the behavior of consumers. Examples more frequently encountered in individuals having difficulty with alcohol are, in particular: one or more anxiety disorders, deficits in the capacities to manage stress and anxiety. The main objective of this work was to study in vivo the anti-addiction effect and hepatotoxicity of tow baclofen analogues complexed with β-Cyclodextrin (βCD) on an alcohol-dependent rat model. Materials and Methods: The synthesis of two analogues, ABF1 and ABF2, close to baclofen was reported. The structural determination of the two compounds was confirmed by NMR and IR analysis. The complexation of analogues with β-Cyclodextrin (βCD) was performed in water at room temperature (25 °C). The interactions of ABF with β-Cyclodextrin, and the stability constant (Ka) of the inclusion complex formed between them were investigated by using UV-visible spectroscopy. The biological effects of baclofen and the two analogues on alcohol dependence were studied in wistar rats. The anti-addiction effect of the analogues was tested by measuring the alcohol intake and the variation of the animal behaviour. The toxicity of the compounds was also analysed on liver injury markers. Results: The amino-3-phenylbutanoic acid (ABF1) and 3,4,5-trihydroxy-N-(methyl-2-acetate) benzamide (ABF2) were synthesized. The complexation of both analogues of baclofen (BF) with β-cyclodextrin (βCD) (ABF-βCD) was realized and confirmed by the stability constant of the inclusion complex (Ka) and Job’s method. The evaluation of anti-addiction activity in vivo showed that ABF1-βCD inhibits the consumption of alcohol at doses equivalent to those of baclofen. Both baclofen analogues have shown an anxiolytic effect. Regarding the toxicity of the two compounds, our results showed that ABF1-βCD has less toxic effect than baclofen; it reduces the activity of ALT and AST enzymes. Histologically, ABF1-βCD has no effect on the liver structure and has a protective effect against lesions alcohol-induced liver disease. Conclusion: Therefore, it can be suggested that ABF1 analogue combined with β-Cyclodextrin can be used as a treatment for alcohol dependence. Further clinical works are needed to confirm its effectiveness.
Keniche, Assia,El Ouar, Ibtissem,Zeghina, Ibtissem,Dib, Mohammed El Amine
p. 187 - 196
(2022/02/02)

Synthesis method of 4-phenyl-2-pyrrolidone
The invention discloses a synthesis method of 4-phenyl-2-pyrrolidone, which comprises the following steps: by using diethyl malonate and 2-nitro-1-phenethyl ketone as raw materials, carrying out condensation reaction by using a strong Lewis base to obtain an intermediate 1, and reacting the intermediate 1 in an organic solvent under the action of palladium-carbon catalytic hydrogenation to obtain an intermediate 3-(3-methoxy carboxyl -4-phenyl-2-pyrrolidone); and finally, carrying out decarboxylation reaction under the alkaline condition of an organic solvent to obtain the final 4-phenyl-2-pyrrolidone. In addition, 4-phenyl-2-pyrrolidone can also be prepared through a Fork alkylation reaction of pyrrolidone and halogenated benzene by a one-step method. The method disclosed by the invention has the characteristics of readily available raw materials, simple reaction conditions, high yield and the like.
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Paragraph 0008; 0029-0037

(2021/04/07)

Assembling of medium/long chain-based β-arylated unnatural amino acid derivatives via the Pd(II)-catalyzed sp3 β-C-H arylation and a short route for rolipram-type derivatives
In this paper, we report the assembling of libraries of β-arylated short/medium/long chain-based non-α-amino acid (aminoalkanoic acid) derivatives via the Pd(II)-catalyzed, bidentate directing group 8-aminoquinoline-aided sp3 β-C-H activation/arylation method. Short/medium chain-based unnatural amino acid derivatives containing an aryl group at the β-position are promising small molecules with therapeutic properties. Thus, it is necessary to enrich the libraries of short/medium/long chain-based unnatural amino acid derivatives containing an aryl group at the β-position. Considering the importance of β-arylated short/medium/long chain-based non-α-amino acid derivatives, an inclusive attention was paid to explore the Pd(II)-catalyzed sp3 β-C-H arylation of short/medium/long chain-based non-α-amino acids. Representative synthetic transformations including a short route for the assembling of rolipram and related compounds and 3-arylated GABA derivatives such as, baclofen, phenibut and tolibut were shown using selected β-C-H arylated non-α-amino acid derivatives.
Tomar, Radha,Bhattacharya, Debabrata,Babu, Srinivasarao Arulananda
p. 2447 - 2465
(2019/03/26)

New multicomponent reaction for the direct synthesis of β-aryl-γ-nitroesters promoted by hydrotalcite-derived mixed oxides as heterogeneous catalyst
A new approach based on multicomponent/domino combined reactions for the synthesis of γ-nitroesters promoted by a mixed aluminium-magnesium oxides derived from hydrotalcite-like material was developed. Different γ-nitroesters were synthesized in 15-95percent yield using Meldrum's acid, aromatic aldehydes, nitromethane and different alcohols as reagents and solvents. The γ-aminobutyric acid derivatives, Phenibut and Baclofen, were prepared in 63 and 61percent overall yield, respectively, through a two steps synthetic strategy. A mechanistic pathway was proposed based on the gas chromatography mass spectrometry (GC-MS) and electrospray ionization mass spectrometry (ESI-MS) experiments.
D'Oca, Caroline R. M.,Naciuk, Fabricio F.,Silva, Jéssica C.,Guedes, Esthéfani P.,Moro, Celso C.,D'Oca, Marcelo G. M.,Santos, Leonardo S.,Natchigall, Fabiane M.,Russowsky, Dennis
p. 285 - 298
(2016/12/18)

Method for preparing phenyl piracetam
The invention discloses a method for preparing phenyl piracetam, and belongs to the field of compound preparing. The method includes the following steps that alkali, cinnamic acid alkyl ester and nitromethane are subjected to an addition reaction to obtain 4-nitryl-3-phenylbutyric acid alkyl ester; after nitryl of the 4-nitryl-3-phenylbutyric acid alkyl ester is reduced with a reducing agent, the reduced nitryl and carbonyl are cyclized, and 4-phenyl-2-pyrrolidone is obtained; alkali, haloacetic acid alkyl ester and the 4-phenyl-2-pyrrolidone are subjected to an alkylation reaction to obtain 4-phenyl-2-pyrrolidone-1-acetic acid alkyl ester; the 4-phenyl-2-pyrrolidone-1-acetic acid alkyl ester and ammonia gas are reacted to obtain the phenyl piracetam. The method has the advantages of being short in reaction step, high in atom utilization, more environmentally friendly, safe in operation, high in reaction yield and purity, beneficial for achieving industrialization an the like.
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Paragraph 0036; 0037; 0038; 0039; 0040; 0041-0050

(2017/05/09)

Efficient synthesis of β-aryl-γ-lactams and their resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen
An efficient synthesis of enantiomerically-pure β-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of β-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.
Montoya-Balbás, Iris J.,Valentín-Guevara, Berenice,López-Mendoza, Estefanía,Linzaga-Elizalde, Irma,Ordo?ez, Mario,Román-Bravo, Perla
p. 22028 - 22043
(2016/01/25)

One pot domino reaction accessing γ-nitroesters: Synthesis of GABA derivatives
Michael addition of 1,3-dicarbonyl compounds to nitrostyrenes is efficiently promoted by hydrotalcite [Mg-Al] to afford the respective γ-nitrodicarbonyl adducts. Differently, the addition of Meldrum's acid leads to a direct access of γ-nitroesters through a one pot domino process. GABA derivatives (+/-)-phenibut and (+/-)-baclofen were readily synthesized from the respective nitro adducts.
Naciuk, Fabricio F.,Vargas, Debora Z.,D'oca, Caroline R. M.,Moro, Celso C.,Russowsky, Dennis
p. 1643 - 1653
(2015/03/18)

Chemical assembly systems: Layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients
While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels - choice of starting material, reagent, or order of reaction modules - enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49-75%).
Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
supporting information
p. 678 - 682
(2015/03/04)

Multisite organic-inorganic hybrid catalysts for the direct sustainable synthesis of GABAergic drugs
Multisite organic-inorganic hybrid catalysts have been prepared and applied in a new general, practical, and sustainable synthetic procedure toward industrially relevant GABA derivatives. The domino sequence is composed of seven chemical transformations which are performed in two one-pot reactions. The method produces both enantiomeric forms of the product in high enantiopurity as well as the racemate in good yields after a single column purification step. This protocol highlights major process intensification, catalyst recyclability, and low waste generation.
Leyva-Perez, Antonio,Garcia-Garcia, Pilar,Corma, Avelino
supporting information
p. 8687 - 8690
(2014/08/18)

Discovery of heterocyclic nonacetamide synaptic vesicle protein 2A (SV2A) ligands with single-digit nanomolar potency: Opening avenues towards the first SV2A positron emission tomography (PET) ligands
The role of the synaptic vesicle protein 2A (SV2A) protein, target of the antiepileptic drug levetiracetam, is still mostly unknown. Considering its potential to provide in vivo functional insights into the role of SV2A in epileptic patients, the development of an SV2A positron emission tomography (PET) tracer has been undertaken. Using a 3D pharmacophore model based on close analogues of levetiracetam, we report the rationale design of three heterocyclic non-acetamide lead compounds, UCB-A, UCB-H and UCB-J, the first single-digit nanomolar SV2A ligands with suitable properties for development as PET tracers. Avenues towards imaging... of synaptic vesicle protein 2A (SV2A) in vivo were opened after the rationale discovery of the first non-acetamide SV2A ligands, displaying single-digit nanomolar potency, using a 3D pharmacophore model. An extensive profiling of the most potent compounds allowed the identification of three leads (see figure) as potential candidates for positron emission tomography (PET) ligand development.
Mercier, Joel,Archen, Laurence,Bollu, Veronique,Carre, Stephane,Evrard, Yves,Jnoff, Eric,Kenda, Benoit,Lallemand, Benedicte,Michel, Philippe,Montel, Florian,Moureau, Florence,Price, Nathalie,Quesnel, Yannick,Sauvage, Xavier,Valade, Anne,Provins, Laurent
p. 693 - 698
(2014/05/06)

β-Substituted γ-butyrolactams from mucochloric acid: Synthesis of (±)-baclofen and other γ-aminobutyric acids and useful building blocks
In the course of our exploration of the application of mucohalic acids in organic synthesis, we reported the synthesis of α,β-dihalo-α, β-unsaturated γ-butyrolactams by reductive amination of a suitable mucohalic acid and a suitable amine. However, the functionalization of the α- and/or β-halogen was found to be elusive under Suzuki conditions that worked well with the corresponding γ-lactones. Although the corresponding β-aryl derivative was obtained under some of the modified Suzuki conditions tried, the yields were found to be very low. Next, the Suzuki coupling was performed on mucochloric acid prior to the reductive amination step. By careful control of the reaction conditions, only β-substitution was achieved to yield the corresponding β-aryl mucochloric acid. This could then be converted to the corresponding β-substituted γ-butyrolactam by reductive amination with 2,4-dimethoxybenzylamine (DMB-NH2) followed by reduction by nickel boride and subsequent deprotection of the DMB group. The resulting γ-butyrolactam could either be alkylated or hydrolyzed resulting in the corresponding β-substituted γ-aminobutyric acid. This methodology was extended to synthesize (±)-baclofen in five steps starting from mucochloric acid.
Biswas, Kallolmay,Gholap, Rajesh,Srinivas, Padakanti,Kanyal, Sachin,Sarma, Koushik Das
p. 2538 - 2545
(2014/01/06)

Synthesis of 3,3-and 4,4-alkyl-phenyl-substituted pyrrolidin-2-one derivatives
Syntheses of 3,3-and 4,4-alkyl-phenyl-substituted pyrrolidin-2-one derivatives are described. The final compounds were obtained by the reductive cyclization of relevant cyanoalkanoate esters using NaBH4 and CoCl2.6H2O. The obtained pyrroIidin-2-one derivatives are pharmacophoric fragments for the synthesis of various biologically active compounds.
Kulig,Ignasik,Malawska
experimental part
p. 1629 - 1636
(2010/07/06)

2-(CYCLIC AMINO)-PYRIMIDONE DERIVATIVES AS TPK1 INHIBITORS
A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof (I) wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).
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Page/Page column 204-205

(2008/06/13)

A phase-switch purification approach for the expedient removal of tagged reagents and scavengers following their application in organic synthesis
In this paper we wish to report on a variety of expedient chemical transformations and purifications achieved via a generic 'catch and release' methodology, based on a synthetically inert bipyridyl chelating tag that can be selectively captured with a resin-bound copper(II) species. Utilising this approach we are able to derive many of the same benefits associated with both solid phase synthesis and supported reagent methods. The Royal Society of Chemistry 2005.
Siu, Jason,Baxendale, Ian R.,Lewthwaite, Russell A.,Ley, Steven V.
p. 3140 - 3160
(2007/10/03)

Evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase
Syntheses and evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2- imines as inhibitors of nitric oxide synthase (NOS) are discussed. An extensive SAR was established for pyrrolidin-2-imines class of compounds. The amidines came out as the most potent inhibitors in addition to displaying selectivity.
Shankaran,Donnelly, Karla L.,Shah, Shrenik K.,Guthikonda, Ravindra N.,MacCoss, Malcolm,Humes, John L.,Pacholok, Stephen G.,Grant, Stephan K.,Kelly,Wong
p. 4539 - 4544
(2007/10/03)

Radical cyclization in heterocycle synthesis. II. Total synthesis of (±)-anantine and (±)-isoanantine
(+)-Anantine, (±)-isoanantine and related compounds were synthesized via two key reactions, sulfanyl radical addition-cyclization and stereoselective construction of the E-benzylidene moiety.
Naito, Takeaki,Honda, Yuko,Bhavakul, Vanida,Yamaguchi, Sayaka,Fujiwara, Azusa,Miyata, Okiko,Ninomiya, Ichiya
p. 1932 - 1939
(2007/10/03)

Phenyl-Substituted Analogues of Oxotremorine as Muscarinic Antagonists
A series of phenyl-substituted analogues of the muscarinic agent oxotremorine (1) have been prepared.The new compounds (3b-11b and 9c) were assayed for antimuscarinic activity on the isolated guinea pig ileum and in intact mice.They were also evaluated for ability to inhibit the binding of the muscarinic antagonist (-)--N-methylscopolamine to homogenates of the rat cerebral cortex.The phenyl-substituted derivatives were devoid of intrinsic muscarinic activity.Instead, they behaved as competitive muscarinic antagonists in these assays with similar or lower affinity for muscarinic receptors than the corresponding methyl-substituted analogues.The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the bytynyl chain showed the highest antimuscarinic potency with dissociation constants (KD) of 0.10 and 0.20 μM, respectively, in the ileum assay.The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antimuscarinic potency than their corresponding methyl-substituted position isomers.A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.
Nilsson, Bjoern M.,Vargas, Hugo M.,Ringdahl, Bjoern,Hacksell, Uli
p. 285 - 294
(2007/10/02)

Lactam-1-acetic acid carbalkoxymethyl esters and method for preparing same
The present invention relates to organic chemistry. Lactam-1-acetic acid carbalkoxymethyl esters have the following general formula: STR1 wherein with R=H, n=1 or 3; with R=phenyl, n=1; R1 is an alkyl. A method for preparing said compounds comprises reacting lactams of the general formula: STR2 wherein with R=H, n=1 or 3, with R=phenyl n=1, with an alkali in a medium of aprotic solvents at a temperature of from 70° to 130° C., followed by the addition of an alkyl ester of a monohalcacetic acid to the resulting mixture and isolation of the desired product. The compounds according to the present invention are intermediate products in the synthesis of known biologically active substances.
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(2008/06/13)

Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues
Rolipram [(R,S)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone] has been shown to inhibit selectively the cAMP phopshodiesterase (PDE) of vascular smooth muscle. In order to further explore the structural requirements for selective PDE inhibition, we synthesized a series of rolipram derivatives differently substituted either at the pyrrolidinone or at the aromatic ring. Among these compounds, rolipram was the most active compound. Semirigid analogues were prepared and used for an evaluation of the active conformation of rolipram. Structural comparison with two other potent and chemically different smooth muscle cAMP-PDE inhibitors, trequinsin and Ro 20-1724, allows us to propose a first topological model of the smooth muscle cAMP-PDE pharmacophore.
Marivet,Bourguignon,Lugnier,Mann,Stoclet,Wermuth
p. 1450 - 1457
(2007/10/02)