- A facile synthesis of 3-aryl pyroglutamic acid. Facile synthesis of baclofen and chlorpheg
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A facile synthesis of 3-aryl pyroglutamic acids via stepwise [3+2] annulation and desulfonated hydrolysis is reported. Base-induced coupling/cyclization reactions of α-sulfonylacetamide with various β-functional groups of (Z)-2-bromoacrylates yielded three contiguous chiral centers on the polysubstituted pyroglutamates system with trans-trans orientation in a one-pot synthesis. This facile strategy was used to synthesize amino acid derivatives baclofen and chlorpheg.
- Chang, Meng-Yang,Sun, Pei-Pei,Chen, Shui-Tein,Chang, Nein-Chen
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- Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor
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Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5–10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.
- Fuse, Shinichiro,Komuro, Keiji,Otake, Yuma,Masui, Hisashi,Nakamura, Hiroyuki
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supporting information
p. 7525 - 7532
(2021/03/17)
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- 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
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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
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p. 2447 - 2465
(2019/03/26)
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- New multicomponent reaction for the direct synthesis of β-aryl-γ-nitroesters promoted by hydrotalcite-derived mixed oxides as heterogeneous catalyst
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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
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p. 285 - 298
(2016/12/18)
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- Efficient synthesis of β-aryl-γ-lactams and their resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen
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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
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p. 22028 - 22043
(2016/01/25)
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- One pot domino reaction accessing γ-nitroesters: Synthesis of GABA derivatives
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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
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p. 1643 - 1653
(2015/03/18)
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- Multisite organic-inorganic hybrid catalysts for the direct sustainable synthesis of GABAergic drugs
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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
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supporting information
p. 8687 - 8690
(2014/08/18)
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- β-Substituted γ-butyrolactams from mucochloric acid: Synthesis of (±)-baclofen and other γ-aminobutyric acids and useful building blocks
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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
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p. 2538 - 2545
(2014/01/06)
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- ALLOSTERIC PROTEIN KINASE MODULATORS
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The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.
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Page/Page column 45
(2012/03/10)
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- A short, chemoenzymatic route to chiral β-aryl-γ-amino acids using reductases from anaerobic bacteria
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A short chemoenzymatic synthesis of β-aryl-γ-aminobutyric acids has been developed, based on a highly enantioselective biocatalytic reduction of β-aryl-β-cyano-α,β-unsaturated carboxylic acids.
- Fryszkowska, Anna,Fisher, Karl,Gardiner, John M.,Stephens, Gill M.
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supporting information; scheme or table
p. 533 - 535
(2010/05/11)
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- ALLOSTERIC PROTEIN KINASE MODULATORS
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The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.
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Page/Page column 94
(2010/04/30)
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- BIPHENYL DERIVATIVES AS MODULATORS OF THE HISTAMINE-H3 RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
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Biphenyl derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the H3 histamine receptor. (Ia) Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-associated disorders, such as cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness, such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease, pain and the like.
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Page/Page column 77
(2009/06/27)
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- CYCLIC DIARYL ETHER COMPOUNDS AS ANTAGONISTS OF PROSTAGLANDIN D2 RECEPTORS
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Described herein are compounds that are antagonists of PGD2 receptors. Also described are pharmaceutical compositions and medicaments that include the antagonists of PGD2 receptors described herein, as well as methods of using such antagonists of PGD2 receptors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other PGD2-dependent or PGD2-mediated conditions or diseases.
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Page/Page column 217
(2009/10/09)
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- Short synthesis of 4-aryl-3-pyrrolin-2-ones
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A three step, convergent synthesis of 4-aryl-3-pyrrolin-2-ones from a tetramic acid has been developed. The key transformation utilized a Suzuki-Miyaura cross-coupling reaction between a 4-tosyloxy-3-pyrrolin-2-one and an arylboronic acid. This work also
- Yoon-Miller, Sarah J.P.,Opalka, Suzanne M.,Pelkey, Erin T.
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p. 827 - 830
(2007/10/03)
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- Pharmacological evaluation of new baclofen derivatives
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The synthesis and in-vivo central pharmacological properties, in particular antinociceptive activity, of some new baclofen derivatives is described. The delayed antinociceptive activity of the N-trifluoroacetyl analogue of baclofen is also characterized.
- Guillon, Jean,Levasseur, Veronique,Sonnet, Pascal,Stiebing, Silvia,Boulouard, Michel,Dallemagne, Patrick,Quermonne, Marie-Anne,Rault, Sylvain
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p. 243 - 247
(2007/10/03)
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- A simple and efficient new approach to the total synthesis of (±)-4- amino-3-(4-chlorophenyl)-butyric acid (BACLOFEN)
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Based on the utilization of a [2+21 cycloaddition reaction between dichloroketene and an appropriated olefin as a key step, we describe a new and simple four step approach to the total synthesis of (±)-4-amino-3-(4- chlorophenyl)-butyric acid (BACLOFEN),
- Coelho, Fernando,De Azevedo, Mariangela B. M.,Boschiero, Roberta,Resende, Patricia
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p. 2455 - 2465
(2007/10/03)
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- An efficient synthesis of (±)-4-amino-3-(4-chlorophenyl)-butyric acid. (baclofen)
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A new preparation of baclofen is proposed. The key step involved a regioselective ring opening of 2-phenylaziridine with allylmagnesium bromide. Further oxidation of the side chain gives access to 4-phenyl-pyrrolidin-2-one and to baclofen.
- Ibuka,Schoenfelder,Bildstein,Mann
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p. 1777 - 1782
(2007/10/02)
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- Synthesis and muscle relaxant activity of cyclic baclofen analogues
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Some new cyclic analogues of baclofen have been prepared and characterized, starting from 4-(4-chlorophenyl)-pyrrolidone. When tested in comparison with the parent compound, they exhibited only a moderate muscle relaxant activity.
- Pifferi,Nizzola,Cristoni
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p. 453 - 455
(2007/10/02)
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- Metabolism of 3-(p-chlorophenyl)pyrrolidine. Structural effects in conversion of a prototype γ-aminobutyric acid prodrug to lactam and γ-aminobutyric acid type metabolites
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By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1) underwent a series of α-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one (6); and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5>10 and 6>11) with the exception of the liver homogenate mitochondrial fraction (611). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.
- Wall,Baker
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p. 1340 - 1348
(2007/10/02)
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- FACILE SYNTHESIS OF γ-, δ-, AND ε-LACTAMS BY CYCLODEHYDRATION OF ο-AMINO ACIDS ON ALUMINA OR SILICA GEL
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It has been found that γ-, δ-, and ε-amino acids cyclodehydrate easily to their corresponding lactams by the action of alumina or silica gel in boiling toluene.
- Blade-Font, Artur
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p. 2443 - 2446
(2007/10/02)
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