127053-22-9Relevant articles and documents
Carbon-Carbon bond cleavage in activation of the prodrug nabumetone
Varfaj, Fatbardha,Zulkifli, Siti N. A.,Park, Hyoung-Goo,Challinor, Victoria L.,De Voss, James J.,De Montellano, Paul R. Ortiz
, p. 828 - 838 (2014)
Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17b-lyase (CYP17), and aromatase (CYP19). Because of the high substrate specificities of these enzymes and the complex nature of their substrates, these reactions have been difficult to characterize. A CYP1A2-catalyzed carbon-carbon bond cleavage reaction is required for conversion of the prodrug nabumetone to its active form, 6-methoxy-2-naphthylacetic acid (6-MNA). Despite worldwide use of nabumetone as an anti-inflammatory agent, the mechanism of its carbon-carbon bond cleavage reaction remains obscure. With the help of authentic synthetic standards, we report here that the reaction involves 3-hydroxylation, carbon-carbon cleavage to the aldehyde, and oxidation of the aldehyde to the acid, all catalyzed by CYP1A2 or, less effectively, by other P450 enzymes. The data indicate that the carbon-carbon bond cleavage is mediated by the ferric peroxo anion rather than the ferryl species in the P450 catalytic cycle. CYP1A2 also catalyzes O-demethylation and alcohol to ketone transformations of nabumetone and its analogs.
Process research and structural studies on nabumetone
Prabhakar,Reddy, C. Bakki,Reddy, Ch. Maheedhara,Nageshwar,Devi, A. Sivalakshmi,Babu, J. Moses,Vyas,Sarma,Reddy
, p. 121 - 125 (1999)
A short, simple and economical process for large-scale preparation of nabumetone has been developed. The single-crystal structures of nabumetone and one of its key intermediates have been determined by X-ray diffraction studies. Two impurities have been isolated and characterised.
An efficient benchtop system for multigram-scale kinetic resolutions using aldolase antibodies
Turner, James M.,Bui, Tommy,Lerner, Richard A.,Barbas III, Carlos F.,List, Benjamin
, p. 2772 - 2774 (2000)
The preparative scale kinetic resolution of racemic aldols 1-4 using aldolase antibodies 38C2 (Aldrich no. 47995-0) and 84G3 (Aldrich no. 52785-8) is described. These reactions use a biphasic aqueous/organic solvent system that allows the catalyst to be reused. Reaction scales range from miligrams to grams, with 0.0086 to 0.12 mol% of antibody binding sites. Because antibodies 38C2 and 84G3 have opposite enantioselectivities, both aldol product enantiomers are accessible by kinetic resolution.
Breaking the Dogma of Aldolase Specificity: Simple Aliphatic Ketones and Aldehydes are Nucleophiles for Fructose-6-phosphate Aldolase
Roldán, Raquel,Sanchez-Moreno, Israel,Scheidt, Thomas,Hélaine, Virgil,Lemaire, Marielle,Parella, Teodor,Clapés, Pere,Fessner, Wolf-Dieter,Guérard-Hélaine, Christine
, p. 5005 - 5009 (2017)
d-Fructose-6-phosphate aldolase (FSA) was probed for extended nucleophile promiscuity by using a series of fluorogenic substrates to reveal retro-aldol activity. Four nucleophiles ethanal, propanone, butanone, and cyclopentanone were subsequently confirmed to be non-natural substrates in the synthesis direction using the wild-type enzyme and its D6H variant. This exceptional widening of the nucleophile substrate scope offers a rapid entry, in good yields and high stereoselectivity, to less oxygenated alkyl ketones and aldehydes, which was hitherto impossible.
Organocatalytic diastereo- And enantioselective oxa-hetero-Diels-Alder reactions of enones with aryl trifluoromethyl ketones for the synthesis of trifluoromethyl-substituted tetrahydropyrans
Pasha, Maira,Tanaka, Fujie
supporting information, p. 9242 - 9250 (2021/11/16)
Tetrahydropyran derivatives are found in bioactives, and introduction of the trifluoromethyl group into molecules often improves biofunctions. Here we report diastereo- and enantioselective oxa-hetero-Diels-Alder reactions catalyzed by amine-based catalyst systems that afford trifluoromethyl-substituted tetrahydropyranones. Catalyst systems and conditions suitable for the reactions to provide the desired diastereomer products with high enantioselectivities were identified, and various trifluoromethyl-substituted tetrahydropyranones were synthesized with high diastereo- and enantioselectivities. Mechanistic investigation suggested that the reactions involve a [4 + 2] cycloaddition pathway, in which the enamine of the enone acts as the diene and the ketone carbonyl group of the aryl trifluoromethyl ketone acts as the dienophile. In this study, tetrahydropyran derivatives with the desired stereochemistry that are difficult to synthesize by previously reported methods were concisely obtained, and the range of tetrahydropyran derivatives that can be synthesized was expanded. This journal is
A CATALYST FOR ONE POT SYNTHESIS OF NABUMETONE AND PROCESS OF PREPARATION THEREOF
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Page/Page column 2; 13-17, (2020/11/30)
The present invention relates to novel heterogeneous catalyst composition for selective synthesis of Nabumetone in one pot process and process to prepare the catalyst. The present invention provides a novel catalyst comprises of Lanthanum, Magnesium, and Nickel particles doped on specific type of silica support, preferably that the support is in amorphous nature. The catalyst is having bifunctional condensation and hydrogenation properties for one pot synthesis of Nabumetone comprising of: Nickel and Lanthanum-magnesium mixed oxide on support of mesoporous silica; Wherein 25 to 30 % w/w of Lanthanum-magnesium mixed oxide are entrapped in pores and surface of support is coated with 3 to 5% w/w Nickel with the result that it prevent the leaching of Lanthanum-magnesium mixed oxide in reaction medium and provides reusability of catalyst.
Enantiocomplementary synthesis of γ-nitroketones using designed and evolved carboligases
Garrabou, Xavier,Verez, Rebecca,Hilvert, Donald
supporting information, p. 103 - 106 (2017/05/16)
Artificial enzymes created by computational design and directed evolution are versatile biocatalysts whose promiscuous activities represent potentially attractive starting points for divergent evolution in the laboratory. The artificial aldolase RA9S.5-8, for example, exploits amine catalysis to promote mechanistically diverse carboligations. Here we report that RA95.5-8 variants catalyze the asymmetric synthesis of γ-nitroketones via two alternative enantiocomplementary Michael-type reactions: enamine-mediated addition of acetone to nitrostyrenes, and nitroalkane addition to conjugated ketones activated as iminium ions. In addition, a cascade of three aldolasecatalyzed reactions enables one-pot assembly of γ-nitroketones from three simpler building blocks. Together, our results highlight the chemical versatility of artificial aldolases for the practical synthesis of important chiral synthons.
Copper-catalyzed retro-aldol reaction of β-hydroxy ketones or nitriles with aldehydes: Chemo- and stereoselective access to (E)-enones and (E)-acrylonitriles
Zhang, Song-Lin,Deng, Zhu-Qin
, p. 7282 - 7294 (2016/08/05)
A copper-catalyzed transfer aldol type reaction of β-hydroxy ketones or nitriles with aldehydes is reported, which enables chemo- and stereoselective access to (E)-α,β-unsaturated ketones and (E)-acrylonitriles. A key step of the in situ copper(i)-promoted retro-aldol reaction of β-hydroxy ketones or nitriles is proposed to generate a reactive Cu(i) enolate or cyanomethyl intermediate, which undergoes ensuing aldol condensation with aldehydes to deliver the products. This reaction uses 1.2 mol% Cu(IPr)Cl (IPr denotes 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) as the catalyst in the presence of 6.0 mol% NaOtBu cocatalyst at room temperature or 70 °C. A range of aryl and heteroaryl aldehydes as well as acrylaldehydes are compatible with many useful functional groups being tolerated. Under the mild and weakly basic conditions, competitive Cannizzaro-type reaction of benzaldehydes and side reactions of base-sensitive functional groups can be effectively suppressed, which show synthetic advantages of this reaction compared to classic aldol reactions. The synthetic potential of this reaction is further demonstrated by the one-step synthesis of biologically active quinolines and 1,8-naphthyridine in excellent yields (up to 91%). Finally, a full catalytic cycle for this reaction has been constructed using DFT computational studies in the context of a retro-aldol/aldol two-stage mechanism. A rather flat reaction energy profile is found indicating that both stages are kinetically facile, which is consistent with the mild reaction conditions.
A promiscuous de Novo retro-aldolase catalyzes asymmetric michael additions via Schiff base intermediates
Garrabou, Xavier,Beck, Tobias,Hilvert, Donald
supporting information, p. 5609 - 5612 (2015/10/12)
Recent advances in computational design have enabled the development of primitive enzymes for a range of mechanistically distinct reactions. Here we show that the rudimentary active sites of these catalysts can give rise to useful chemical promiscuity. Sp
A scalable two-step continuous flow synthesis of nabumetone and related 4-aryl-2-butanones
Viviano, Monica,Glasnov, Toma N.,Reichart, Benedik,Tekautz, Guenter,Kappe, C. Oliver
experimental part, p. 858 - 870 (2012/06/30)
Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether [4-(4-methoxyphenyl)-2-butanone] were evaluated. All three protocols involve the initial preparation of the corresponding 4-aryl-3-buten-2-ones via Mizoroki-Heck, Wittig, or aldol strategies, which is then followed by selective hydrogenation of the C=C double bond to the desired 4-aryl-2-butanones. The synthetic routes to 4-aryl-3-buten-2-ones were first optimized/intensified on small scale to reaction times of 1-10 min using batch microwave heating technology and then translated to a scalable continuous flow process employing commercially available stainless steel capillary tube reactors. For the synthesis of 4-(4-methoxyphenyl)-3-buten-2-one a further scale-up using a custom-built mesofluidic mini-plant flow system capable of processing several liters per hour was designed to further expand the scale of the process. The final hydrogenation step was performed using a fixed-bed continuous flow hydrogenator employing Ra/Ni as a catalyst.
