- Site-Specific Oxidation of (sp3)C-C(sp3)/H Bonds by NaNO2/HCl
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A site-specific oxidation of (sp3)C-C(sp3) and (sp3)C-H bonds in aryl alkanes by the use of NaNO2/HCl was explored. The method is chemical-oxidant-free, transition-metal-free, uses water as the solvent, and proceeds under mild conditions, making it valuable and attractive to synthetic organic chemistry.
- Zhao, Jianyou,Shen, Tong,Sun, Zhihui,Wang, Nengyong,Yang, Le,Wu, Jintao,You, Huichao,Liu, Zhong-Quan
-
supporting information
p. 4057 - 4061
(2021/05/26)
-
- Design of multifaceted antioxidants: Shifting towards anti-inflammatory and antihyperlipidemic activity
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Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1-17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.
- Kourounakis, Angeliki,Lambrinidis, George,Tzara, Ariadni
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- Phenyl substituted thiazole linked 1, 2, 4-triazole derivatives: Synthesis and their biological evaluation
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Synthesize and evaluate some phenyl substituted thiazole linked 1, 2, 4-triazole derivatives as antimicrobial agents. Compounds containing 1, 2, 4-triazole moieties are widely used as antimicrobial and antifungal agents whereas thiazole is another heterocyclic ring exhibiting various pharmacological actions. It is interesting to incorporate different bioactive pharmacophores in the same molecular framework to examine cumulative effect exerted by the moiety. This hypothesis was applied in research work by having triazole and thiazole in the same molecular framework. The present work was mainly focused on synthesis of some 1, 2, 4-triazole derivatives linking with phenyl substituted thiazole nucleus and their evaluation for biological activity. The compounds (8a-8j) were synthesized as per design scheme and elucidated their structures using different spectroscopic data of IR, 1HNMR, 13CNMR & mass spectroscopy. These synthesized derivatives were evaluated for their antibacterial activity using broth dilution assay. Further, mechanism of action of test compounds was examined using protein leakage assay. All the spectral data were confirmed the synthesis of phenyl substituted thiazole linked 1, 2, 4-triazole derivatives and some of them exhibited significant antimicrobial activity. Amongst all compound 8c showed most potent activity with lowest IC50 values 180 μg/ml and 120 μg/ml against S. aureus & amp; B. cereus respectively. Whereas compound 8j demonstrated strong inhibitory activities only against negative strains P. aeruginosa and E. coli with lowest IC50 values 240 μg/mL and 200μg/mL respectively.
- Jain, Sonika,Dhall, Esha,Devi, Meenu,Sharma, Swapnil,Dwivedi, Jaya,Sahu, Sanjeev Kumar
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p. 727 - 734
(2021/09/30)
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- Reshaping the active pocket of esterase Est816 for resolution of economically important racemates
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Bacterial esterases are potential biocatalysts for the production of optically pure compounds. However, the substrate promiscuity and chiral selectivity of esterases usually have a negative correlation, which limits their commercial value. Herein, an efficient and versatile esterase (Est816) was identified as a promising catalyst for the hydrolysis of a wide range of economically important substrates with low enantioselectivity. We rationally designed several variants with up to 11-fold increased catalytic efficiency towards ethyl 2-arylpropionates, mostly retaining the initial substrate scope and enantioselectivity. These variants provided a dramatic increase in efficiency for biocatalytic applications. Based on the best variant Est816-M1, several variants with higher or inverted enantioselectivity were designed through careful analysis of the structural information and molecular docking. Two stereoselectively complementary mutants, Est816-M3 and Est816-M4, successfully overcame and even reversed the low enantioselectivity, and several 2-arylpropionic acid derivatives with highEvalues were obtained. Our results offer potential industrial biocatalysts for the preparation of structurally diverse chiral carboxylic acids and further lay the foundation for improving the catalytic efficiency and enantioselectivity of esterases.
- Fan, Xinjiong,Fu, Yao,Liu, Xiaolong,Zhao, Meng
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p. 6126 - 6133
(2021/09/28)
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- Ibuprofen-based chemosensor for efficient binding and sensing of Cu2+ ion in aqueous medium
-
An ibuprofen based molecular receptor R1 (N-[2-[(2-Hydroxy-benzylidene)-amino]-ethyl]-2-(4-isobutyl-phenyl)-propionamide) was developed for the detection of Cu2+ ion in aqueous medium by absorbance and fluorescence techniques. Binding constants (4.89–5.67 × 103 M?1) and detection limits (1.71–2.12 μM) showed significant sensing ability. SEM and PXRD techniques were employed to establish the complex formation between R1 and Cu2+ ion and also showed promising behaviour of nanomaterial. The competitive binding experiments showed the selectivity of Cu2+ ion in presence of other metal ions in aquoues medium. The reversibility studies for chemosensor R1 was investigated and EDTA used as restoring agent. The strong chelation through –N and –O atoms of receptor R1 enhance the change in color triggered selectively by Cu2+ ion and detected by colorimetric methods. The theoretical calculations were employed in order to confirm the experimental observations in the molecular frames.
- Hooda, Sunita,Kumar, Pramod,Kumar, Vikrant,Lal, Shyam,Prakash, Kunal
-
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- Radical dehydroxylative alkylation of tertiary alcohols by Ti catalysis
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Deoxygenative radical C?C bond-forming reactions of alcohols are a long-standing challenge in synthetic chemistry, and the current methods rely on multistep procedures. Herein, we report a direct dehydroxylative radical alkylation reaction of tertiary alcohols. This new protocol shows the feasibility of generating tertiary carbon radicals from alcohols and offers an approach for the facile and precise construction of all-carbon quaternary centers. The reaction proceeds with a broad substrate scope of alcohols and activated alkenes. It can tolerate a wide range of electrophilic coupling partners, including allylic carboxylates, aryl and vinyl electrophiles, and primary alkyl chlorides/bromides, making the method complementary to the cross-coupling procedures. The method is highly selective for the alkylation of tertiary alcohols, leaving secondary/primary alcohols (benzyl alcohols included) and phenols intact. The synthetic utility of the method is highlighted by its 10-g-scale reaction and the late-stage modification of complex molecules. A combination of experiments and density functional theory calculations establishes a plausible mechanism implicating a tertiary carbon radical generated via Ti-catalyzed homolysis of the C?OH bond.
- Xie, Hao,Guo, Jiandong,Wang, Yu-Quan,Wang, Ke,Guo, Peng,Su, Pei-Feng,Wang, Xiaotai,Shu, Xing-Zhong
-
supporting information
p. 16787 - 16794
(2020/11/09)
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- Carbonic anhydrase inhibitory potential of 1,2,4-triazole-3-thione derivatives of flurbiprofen, ibuprofen and 4-tert-butylbenzoic hydrazide: Design, synthesis, characterization, biochemical evaluation, molecular docking and dynamic simulation studies
-
Background: The over-expression of the carbonic anhydrases results in some specific carcinomas including pancreatic, gastric and brain tumor. Tumors are distinguished under hypoxic conditions and various investigations are being carried out to target the known hypoxic areas of the tumors to increase the sensitivity towards standard therapeutic treatment. Objective: Herein, we have designed and synthesized some biologically important esters, hydrazides, thiocarbamates, 1,2,4-triazole-3-thiones and Schiff bases. The purpose of the research was to evaluate the derivative against carbonic anhydrase and to assess the toxicity of the same compounds. Method: The structures of all the compounds were characterized by FT-IR, mass spectrometry, elemental analysis, 1H and 13C NMR spectroscopy. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase II by in vitro assay. Double reciprocal plots for inhibition kinetics of the potent compounds were constructed and mode of inhibition was determined. Furthermore, to check the cytotoxicity, these derivatives were tested against human breast adenocarcinoma by MTT method. Results: X-ray diffraction analysis of the compounds 10, 14 and 15 showed that they did not have any φ-φ or C-H…φ interactions. The experimental results were validated by molecular docking and dynamic simulations of the potent compounds in the active pocket of enzyme. Important binding interactions of potent compounds with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Drug likeness profile of the derivatives was evaluated to determine the physicochemical properties. Conclusion: The proposed synthetic approach provides a suitable platform for the generation of a new library of compounds which could potentially be employed in the future testing and optimization of inhibitor potencies.
- Abbas, Saghir,Abbas, Syed M.,Ali, Saqib,Hameed, Shahid,Iqbal, Jamshed,Munawar, Khurram S.,Shaheen, Farzana,Tahir, Muhammad N.,Ur Rahman, Shafiq,Zaib, Sumera
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p. 298 - 310
(2019/07/12)
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- Synthesis and Evaluation of Some Phenyl Substituted Azetidine Containing 1, 2, 4-triazole Derivatives as Antibacterial Agents
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A novel series of phenyl substituted azetidine containing 1, 2, 4-triazole derivatives 7(a–j) were synthesized and characterized by IR, 1HNMR, 13CNMR, and mass spectroscopy. Synthesized 1, 2, 4-triazole derivatives were subsequently assayed in vitro to investigate their antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli using broth dilution method. Compounds 7c, 7d, and 7e exhibited potent inhibitory activities as compared to standard cefotaxime. Further, fluorescence spectral studies were also carried out to ascertain the antibacterial potential of compound 7c against two bacterial strains, that is, P.?aeruginosa and S.?aureus. In docking studies, all the compounds exhibited good docking scores between ?12.04 and ?11.36?kcal/mol and indicated that compounds could act through inhibition of bacterial DNA gyrase (PDB ID 3U2D). Among all, 7c has shown the maximum docking score and found in agreement to in vitro studies. In conclusion, synthesized 1, 2, 4-triazole derivatives holds substantial caliber to be categorized as antibacterial agents.
- Dhall, Esha,Jain, Sonika,Mishra, Achal,Dwivedi, Jaya,Sharma, Swapnil
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p. 2859 - 2869
(2018/11/10)
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- Efficient resolution of profen ethyl ester racemates by engineered Yarrowia lipolytica Lip2p lipase
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Enzyme-catalyzed enantiomer discrimination is still a great challenge for the development of industrial pharmaceutical processes. For the resolution of ibuprofen, naproxen and ketoprofen racemates, three major anti-inflammatory drugs, only lipases from Candida rugosa present a high selectivity if solvent and surfactant use is discarded. However, their catalytic activities are too low. In the present work, we demonstrate that the lipase Lip2p from the yeast Yarrowia lipolytica has a higher catalytic activity than C. rugosa lipases to hydrolyze the ethyl esters of ibuprofen, naproxen and ketoprofen, but its selectivity is not sufficient [E?=?52 (S); 11 (S) and 1.5 (R) respectively]. The enantioselectivity was further improved by site-directed mutagenesis, targeted at the substrate binding site and guided by molecular modelling studies. By investigating the binding modes of the (R)- and (S)-enantiomers in the active site, two amino acid residues located in the hydrophobic substrate binding site of the lipase, namely residues 232 and 235, were identified as crucial for enantiomer discrimination and enzyme activity. The (S) enantioselectivity of Lip2p towards ethyl ibuprofen esters was rendered infinite (E???300) by replacing V232 by an A or C residue. Substitution of V235 by C, M, S, or T amino acids led to a great increase in the (S)-enantioselectivity (E???300) towards naproxen ethyl ester. Finally, the variant V232F enabled the efficient kinetic resolution of ethyl ketoprofen ester enantiomers [(R)-enantiopreference; E???300]. In addition to the increase in selectivity, a remarkable increase in velocity by 2.6, 2.7 and 2.5?times, respectively, was found for ibuprofen, naproxen and ketoprofen ethyl esters.
- Gérard, Doriane,Guéroult, Marc,Casas-Godoy, Leticia,Condoret, Jean-Stéphane,André, Isabelle,Marty, Alain,Duquesne, Sophie
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p. 433 - 441
(2017/03/24)
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- Synthesis, characterization, and biological evaluation of furoxan coupled ibuprofen derivatives as anti-inflammatory agents
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A series of furoxan-based nitric oxide releasing ibuprofen derivatives were synthesized and tested for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, and hepatotoxic properties. The compounds exhibited more protection than ibuprofen with regard to gastric toxicity. Among the tested compounds 4-[2-[2-(4-isobutylphenyl)propanamido]ethoxycarbonyl]-3-methylfuroxan and 4-[2-[2-(4-isobutylphenyl)propanoyl]hydrazinecarbonyl]-3-phenylfuroxan emerged as most active anti-inflammatory agents with reduced gastrotoxicity. The results showed that incorporation of NO donating group caused a moderate increase in anti-inflammatory activity with a marked decrease in gastric ulcerations compared to their parent drug ibuprofen. A molecular docking study of all the compounds was also performed to provide the binding modes of COX-1 enzyme. Among all the titled compounds, 4-[2-[2-(4-isobutylphenyl)propanamido]ethoxycarbonyl]-3-methylfuroxan was found to be most potent and have high docking score showing favorable orientation within the COX-1 binding site.
- Amir, Mohd,Akhter, Mohd Wasim,Alam, Ozair
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p. 493 - 508
(2016/03/19)
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- Novel hybrid-pyrrole derivatives: Their synthesis, antitubercular evaluation and docking studies
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Using novel hybrid molecules for the treatment of tuberculosis is one of the latest approaches. Keeping this concept in mind, thirty two hybrid compounds were synthesized, with pyrrole as one of the moieties, clubbed to coumarin, ibuprofen and isoniazid. The compounds were evaluated against Mycobacterium tuberculosis H37Rv strain. Compounds 7e and 8e exhibited MIC of 3.7 and 5.10 μg mL-1 and growth inhibition of 95% and 92%, respectively. These compounds were also active against single drug resistant bacterial strains. The compounds were devoid of cytotoxicity when tested against Vero African green monkey kidney cell line. Docking study was carried out on enoyl acyl carrier protein enzyme to provide some understanding into the mechanism of action of these compounds.
- Saha, Rikta,Alam, Md. Mumtaz,Akhter, Mymoona
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p. 12807 - 12820
(2015/02/19)
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- Synthesis and biological evaluation of new 1,3-Thiazolidine-4-one Derivatives of 2-(4-Isobutylphenyl)propionic Acid
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New thiazolidine-4-one derivatives of 2-(4-isobutylphenyl)propionic acid (ibuprofen) have been synthesized as potential anti-inflammatory drugs. The structure of the new compounds was proved using spectral methods (FR-IR, 1H-NMR, 13C-NMR, MS). The in vitro antioxidant potential of the synthesized compounds was evaluated according to the total antioxidant activity, the DPPH and ABTS radical scavenging assays. Reactive oxygen species (ROS) and free radicals are considered to be involved in many pathological events like diabetes mellitus, neurodegenerative diseases, cancer, infections and more recently, in inflammation. It is known that overproduction of free radicals may initiate and amplify the inflammatory process via upregulation of genes involved in the production of proinflammatory cytokines and adhesion molecules. The chemical modulation of acyl hydrazones of ibuprofen 3a-l through cyclization to the corresponding thiazolidine-4-ones 4a-n led to increased antioxidant potential, as all thiazolidine-4-ones were more active than their parent acyl hydrazones and also ibuprofen. The most active compounds are the thiazolidine-4-ones 4e, m, which showed the highest DPPH radical scavenging ability, their activity being comparable with vitamin E.
- Vasincu, Ioana Mirela,Apotrosoaei, Maria,Panzariu, Andreea-Teodora,Buron, Frdric,Routier, Sylvain,Profire, Lenuta
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p. 15005 - 15025
(2015/02/19)
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- Enantioselective resolution of racemic ibuprofen esters using different lipases immobilized on octyl sepharose
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Here we report the stereoselective hydrolysis of racemic esters catalyzed by Candida rugosa lipase (CRL) and Rhizopus oryzae lipase (ROL) immobilized on octyl-sepharose via physical adsorption. Hydrophobic immobilization caused to almost six fold hyperactivation with 229.2 and 81.3 U/mg enzyme for immobilized CRL and ROL, respectively (13.2 and 48.75 U/mg for corresponding free enzyme). Based on the preliminary results, CRL was chosen for further investigation. The performance and yield of the reaction were evaluated as a function of the critical reaction parameters such as temperature, enzyme to substrate ratio and organic co-solvent. An increase in the temperature resulted to decrease in enantioselectivity of hydrolysis reaction. The hydrolysis reactions were carried out in presence of two organic solvents; n-hexane and isooctane. Generally n-hexane was a better co-solvent compared to isooctane. High enantioselective hydrolysis of the racemic esters (yielding S(+) ibuprofen; ee ≤ 95%) can be achieved using the immobilized CRL. Among various esters the kinetic resolution of ibuprofen butyl ester yielded the best results (E value 70 and 74; conversion 14.6 and 8.9 in n-hexane and isooctane, respectively). The immobilized derivatives were re-used in four cycles and showed little decrease in enantiomeric excess of (S)-ibuprofen. 96.7 eep and conversion 14.6 in first cycle reached to 90.5 eep and conversion 11.3 in the forth cycle.
- Yousefi, Maryam,Mohammadi, Mehdi,Habibi, Zohreh
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-
- A new ibuprofen derivative inhibits platelet aggregation and ros mediated platelet apoptosis
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Thrombocytopenia is a serious issue connected with the pathogenesis of several human diseases including chronic inflammation, arthritis, Alzheimer's disease, cardiovascular diseases (CVDs) and other oxidative stress-associated pathologies. The indiscriminate use of antibiotics and other biological drugs are reported to result in thrombocytopenia, which is often neglected during the treatment regime. In addition, augmented oxidative stress induced by drugs and pathological conditions has also been shown to induce thrombocytopenia, which seems to be the most obvious consequence of elevated rate of platelet apoptosis. Thus, blocking oxidative stress-induced platelet apoptosis would be of prime importance in order to negotiate thrombocytopenia and associated human pathologies. The current study presents the synthesis and platelet protective nature of novel ibuprofen derivatives. The potent anti-oxidant ibuprofen derivative 4f was selected for the study and the platelet protective efficacy and platelet aggregation inhibitory property has been demonstrated. The compound 4f dose dependently mitigates the oxidative stress-induced platelet apoptosis in both platelet rich plasma and washed platelets. The platelet protective nature of compound 4f was determined by assessing various apoptotic markers such as ROS generation, cytosolic Ca2+levels, PS externalization, cytochrome C translocation, Caspase activation, mitochondrial membrane depolarization, cytotoxicity, LDH leakage and tyrosine phosphorylation of cytosolic proteins. Furthermore, compound 4f dose dependently ameliorated agonist induced platelet aggregation. Therefore, compound 4f can be estimated as a potential candidate in the treatment regime of pathological disorders associated with platelet activation and apoptosis. In addition, compound 4f can be used as an auxiliary therapeutic agent in pathologies associated with thrombocytopenia.
- Rakesh, Kodagahalli S.,Jagadish, Swamy,Vinayaka, Ajjampura C.,Hemshekhar, Mahadevappa,Paul, Manoj,Thushara, Ram M.,Sundaram, Mahalingam S.,Swaroop, Toreshettahally R.,Mohan, Chakrabhavi D.,Basappa,Sadashiva, Marilinganadoddi P.,Kemparaju, Kempaiah,Girish, Kesturu S.,Rangappa, Kanchugarakoppal S.
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p. e2718 - e2718
(2015/06/01)
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- Synthesis and Pharmacological Evaluation of New Chemical Entities from Ibuprofen as Novel Analgesic Candidates
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Non-steroidal anti-inflammatory drugs (NSAIDs) are the first choice of drugs that are normally used for the treatment of pain and inflammation. Ibuprofen (I) and its analogues as the most widely used NSAIDs have been synthesized in recent years. In an effort to establish new candidates with improved analgesic properties, derivatives (II-VII) with substituted aromatic as well as aliphatic moieties were synthesized in this experiment and evaluated in formalin test with rats. The results were compared to ibuprofen and control groups. Findings indicated that derivatives with new alkylphenyl rings (VI and VII) had some similar or more analgesic activities relative to the control and ibuprofen groups, respectively; which could be justified as to more alkyl and phenyl groups instead of p-isobutylphenyl moiety in I.
- Ahmadi,Naderi,Daniali,Kazemi,Aazami,Alizadeh,Nahri-Niknafs
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p. 457 - 462
(2015/09/15)
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- PROCESS FOR SYNTHESIZING PHENYLACETIC ACID BY CARBONYLATION OF TOLUENE
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A production process for substituted phenylacetic acids or ester analogues thereof is disclosed. In this process toluene or toluene substituted with various substituents, an alcohol, an oxidant and carbon monoxide are used as raw materials to obtain compounds comprising structure of phenylacetic acid ester or analogues thereof by catalysis of the complex catalyst formed from transition metal and ligand, and such compounds are hydrolyzed to obtain various substituted phenylacetic acid based compounds. This type of compounds and their derivatives serve as important fine chemicals used widely in the industries of pharmaceuticals, pesticides, perfume and the like.
- -
-
Paragraph 0104; 0105
(2013/11/19)
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- Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of new 2-(4-isobutylphenyl)propanoic acid derivatives
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Synthesis and pharmacological evaluation of various 2-(4-isobutylphenyl) propanoic acid derivatives containing 1,3,4-thiadiazole and thiadiazolo[3,2-a] [1,3,5]triazine-5-thione nucleus is reported here. The structures of new compounds are supported by IR, 1H & 13C NMR data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA). Compound 4i and 5f showed 89.50 and 88.88% of inhibition in paw edema, 69.80 and 66.25% protection against acetic acid-induced writhings and 0.7 and 0.65 of severity index, respectively, compared to 90.12, 72.50 and 1.95 values of ibuprofen.
- Raval, Jignesh Priyakant,Gandhi, Ankur Navinchandra,Akhaja, Tarunkumar Nanjibhai,Myangar, Kruti Navinbhai,Patel, Nilesh Hasmukhbhai
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scheme or table
p. 110 - 116
(2012/04/18)
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- A new method for production of chiral 2-aryl-2-fluoropropanoic acids using an effective kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids
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We report a new method for the preparation of chiral 2-aryl-2- fluoropropanoic acids, including 2-fluoroibuprofen, a fluorinated analogue of non-steroidal anti-inflammatory drugs (NSAIDs), by the kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids using enantioselective esterification. By applying pivalic anhydride (Piv2O) as a coupling agent, bis(α-naphthyl)methanol [(α-Np)2CHOH] as an achiral alcohol, and (+)-benzotetramisole (BTM) as a chiral acyl-transfer catalyst, a series of racemic 2-aryl-2-fluoropropanoic acids were kinetically separated to afford the optically active carboxylic acids and the corresponding esters with good to high enantiomeric excesses. This technology can provide a convenient approach to furnish the chiral a-fluorinated drugs containing quaternary carbons at the α-positions in the 2-aryl-2-fluoropropanoic acid structure.
- Tengeiji, Atsushi,Shiina, Isamu
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experimental part
p. 7356 - 7378
(2012/09/05)
-
- A novel alkaline esterase from sporosarcina sp. nov. strain eSP04 catalyzing the hydrolysis of a wide variety of aryl-carboxylic acid esters
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A novel esterase showing activity specific for esters of aryl-carboxylic acids was discovered in Sporosarcina sp. nov., which was identified by the 16S rDNA sequencing method in addition to morphological and physiological analyses. The aryl-carboxylesterase (named EstAC) was purified 780-fold from crude cell extracts by a 5-step procedure. EstAC was characterized as a monomeric protein with a molecular weight of 43,000, an optimum pH of around 9.0, and an optimum temperature of 40 °C. The pH optimum and the effects of inhibitors together with an internal amino acid sequence suggested that EstAC is a member of family VIII esterases. EstAC was found to be highly active on a wide variety of substrates such as alkyl benzoates, alkyl phenylacetates, ethyl α- or β-substituted phenylpropionates, dialkyl terephthalates, dimethyl isophthalate, and ethylene glycol dibenzoate. However, monomethyl terephthalate was not hydrolyzed. It was suggested that EstAC had 4-hydroxybenzoyl and cinnamoyl esterase activities as well.
- Takehara, Munenori,Kinoshita, Kaori,Miyamoto, Masahiro,Hirohara, Hideo
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p. 1721 - 1727,7
(2012/12/11)
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- Exclusive aromatic vs aliphatic C-H bond functionalization by carbene insertion with gold-based catalysts
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The direct functionalization of aromatic C-H bonds by carbene insertion from diazo compounds catalyzed by gold complexes with N-heterocyclic ligands is described. The reaction is completely selective toward the C sp2-H bonds, other C sp3-H bonds remaining unreacted. A study with several NHC ligands in Au(I) and Au(III) complexes has been performed. The potential application of this strategy to give profen derivatives has also been explored.
- Rivilla, Ivan,Gomez-Emeterio, B. Pilar,Fructos, Manuel R.,Diaz-Requejo, M. Mar,Perez, Pedro J.
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experimental part
p. 2855 - 2860
(2011/07/08)
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- Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases
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We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto-enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.
- Galletti, Paola,Emer, Enrico,Gucciardo, Gabriele,Quintavalla, Arianna,Pori, Matteo,Giacomini, Daria
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supporting information; experimental part
p. 4117 - 4123
(2010/10/03)
-
- N'-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene] 2/4-substituted hydrazides: Synthesis and anticonvulsant activity
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A series of N'-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene] 2/4-substituted hydrazides were synthesized using appropriate synthetic route and characterized by elemental analysis and spectral data. The anticonvulsant activity of some of the synthesized compounds were evaluated against maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazol (scPTZ) induced seizure models in mice. The neurotoxicity were assessed using the rotorod method. All the test compounds were administered at doses of 30, 100, and 300 mg/kg body weight and the anticonvulsant activity was noted at 0.5 and 4 h time intervals after the drug administration. Among the compound tested, all except 5g showed protection from seizures in both the animal models. Some titled compounds exhibited lesser CNS depression and neurotoxicity compared to phenytoin. A series of substituted hydrazide derivatives were synthesized, evaluated for their anticonvulsant potency in two animal models along with behavioural and neurotoxicity screen and also subjected to computational parameters.
- Kaushik, Darpan,Khan, Suroor Ahmad,Chawla, Gita,Kumar, Suresh
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experimental part
p. 3943 - 3949
(2010/09/11)
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- Design & synthesis of 2-(substituted aryloxy)-5-(substituted benzylidene)-3-phenyl-2,5-dihydro-1H-[1,2,4] triazin-6-one as potential anticonvulsant agents
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A series of 2-(substituted aryloxy)-5-(substituted benzylidene)-3-phenyl-2, 5-dihydro-1H-[1,2,4] triazin-6-one were designed & synthesized using appropriate synthetic route keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and CNS activities. After intraperitoneal injection to mice, some synthesized derivatives were examined in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPTZ) induced seizure and neurotoxicity screens. Those found potent were also evaluated for behavioural impairment and depression activity. Among the compound tested, 5 eIX showed protection from seizures in both the animal models at dose level of 30 mg/kg while 5 bII & 5 cII showed protection against scPTZ model at same dose level. Some titled compounds exhibited lesser CNS depression and neurotoxicity compared to clinically effective drug. A series of substituted [1,2,4] triazin-6-one derivatives were synthesized, evaluated for their anticonvulsant potency on two animal models along with CNS activity and neurotoxicity and also subjected to computational parameter.
- Kaushik, Darpan,Khan, Suroor Ahmad,Chawla, Gita
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experimental part
p. 3960 - 3969
(2010/09/11)
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- Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives
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The acid hydrazides (2) derived from ibuprofen and 4-methylthiophenyl acetic acids have been subjected to cyclization with carbon disulphide under basic conditions to yield 1,3,4-oxadiazol-2-thiones (3) which on aminomethylation with formaldehyde and secondary amines afforded a series of Mannich bases (4 and 5). Purity of the compounds has been confirmed by TLC. Structures of these compounds were established on the basis of elemental analyses and spectral studies. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and antimicrobial activities.
- Manjunatha,Poojary, Boja,Lobo, Prajwal L.,Fernandes, Jennifer,Kumari, N. Suchetha
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scheme or table
p. 5225 - 5233
(2011/01/04)
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- Composition comprising covalent conjugates of chitosan and an acidic drug for parenteral administration
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The present invention relates to a composition comprising an aqueous solvent and a conjugate of at least one hydrophilic polymer having a primary amine functional group, a derivative or monomer thereof and at least one acidic drug; a method for its preparation and use thereof
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Page/Page column title page; 4; 7
(2008/12/07)
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- Aqueous composition comprising chitosan and an acidic drug
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The present invention relates to a composition comprising an aqueous solvent and a conjugate of at least one hydrophilic polymer having a primary amine functional group, a derivative or monomer thereof and at least one acidic drug; a method for its preparation and use thereof.
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Page/Page column title page; 4; 8
(2008/12/07)
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- Composition comprising chitosan and an acidic drug for oral controlled release
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The present invention relates to a composition comprising an aqueous solvent and a conjugate of at least one hydrophilic polymer having a primary amine functional group, a derivative or monomer thereof and at least one acidic drug; a method for its preparation and use thereof.
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Page/Page column title page; 4; 7
(2008/12/07)
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- On the scope of radical reactions in aqueous media utilizing quaternary ammonium salts of phosphinic acids as chiral and achiral hydrogen donors
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A broad range of fundamental free radical reactions such as hydrogen atom transfer, radical deoxygenations, and radical cyclizations utilizing quaternary ammonium salts of phosphinic acids as chiral and achiral hydrogen donors at room temperature are investigated. The reactions proceed in good to excellent yields with some degree of enantioselectivity.
- Perchyonok,Tuck, Kellie L.,Langford, Steven J.,Hearn, Milton W.
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p. 4777 - 4779
(2008/12/22)
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- An efficient laboratory synthesis of α-deuteriated profens
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An efficient and practical laboratory synthesis of a series of 2-deuterio-2-arylpropionic acids (α-deuterioprofens) is described. The levels of deuterium incorporation are high and the products are synthetically useful. Copyright
- Coumbarides, Gregory S.,Dingjan, Marco,Eames, Jason,Flinn, Anthony,Northen, Julian
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p. 903 - 914
(2008/02/09)
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- Trichosporon beigelli esterase (TBE): A versatile esterase for the resolution of economically important racemates
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A hydrolase producing strain Trichosporon beigelli esterase (TBE) isolated from local cottage cheese in its native form has displayed versatility and high efficacy in the kinetic resolution of a wide range of economically important substrates, which include racemic secondary alcohols, such as 1-(6-methoxy-2-naphthyl)ethanol (E ~ 316), 1-(3,4-methylenedioxyphenyl) ethanol and pentanol (E ~ 180 and 156 resp.), and alkyl esters of carboxylic acids such as ibuprofen (E ~ 340), 2-(benzylthio)propanoic acid (E ~ 1000). In other substrates such as in the primary alcohol 2-(6-methoxy-2- naphthyl)propan-1-ol and carboxylic acids such as 2-(5-bromo-6-methoxy-2- naphthyl)propanoic acid, 2-(2-naphthyloxy)propanoic acid, and substituted 2-thiopropanoic acids, it displayed moderate to low selectivity. Commercial lipases such as CCL, PPL, and PSL were also used in the resolution of the substrates for comparative studies.
- Koul, Surrinder,Koul, Jawahir Lal,Singh, Budh,Kapoor, Munish,Parshad, Rajinder,Manhas, Kuldeep S.,Taneja, Subhash C.,Qazi, Ghulam N.
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p. 2575 - 2591
(2007/10/03)
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- KETONE COMPOUNDS AND COMPOSITIONS FOR CHOLESTEROL MANAGEMENT AND RELATED USES
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The present invention relates to novel ketone compounds, compositions comprising ketone compounds, and methods useful for treating and preventing cardiovascular diseases, dyslipidemias, dysproteinemias, and glucose metabolism disorders comprising administering a composition comprising a ketone compound. The compounds, compositions, and methods of the invention are also useful for treating and preventing Alzheimer's disease, Syndrome X, peroxisome proliferator activated receptor-related disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.
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Page/Page column 282-283
(2010/02/13)
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- Long hydrocarbon chain keto diols and diacids that favorably alter lipid disorders in vivo
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Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 10g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.
- Mueller, Ralf,Yang, Jing,Duan, Caiming,Pop, Emil,Geoffroy, Otto J.,Zhang, Lian Hao,Huang, Tian-Bao,Denisenko, Sergey,McCosar, Bruce H.,Oniciu, Daniela C.,Bisgaier, Charles L.,Pape, Michael E.,Freiman, Catherine Delaney,Goetz, Brian,Cramer, Clay T.,Hopson, Krista L.,Dasseux, Jean-Louis H.
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p. 6082 - 6099
(2007/10/03)
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- Ketone compounds and compositions for cholesterol management and related uses
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The present invention relates to novel ketone compounds, compositions comprising ketone compounds, and methods useful for treating and preventing cardiovascular diseases, dyslipidemias, dysproteinemias, and glucose metabolism disorders comprising administering a composition comprising a ketone compound. The compounds, compositions, and methods of the invention are also useful for treating and preventing Alzheimer's Disease, Syndrome X, peroxisome proliferator activated receptor-related disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.
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- C-nitroso compounds and use thereof
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A C-nitroso compound having a molecular weight ranging from about 225 to about 1,000 (from about 225 to about 600 for oral administration) on a monomeric basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, is useful as an NO donor. When the compound is obtained from a carbon acid with a pKa less than about 10, it provides vascular relaxing effect when used at micromolar concentrations and this activity is potentiated by glutathione to be obtained at nanomolar concentrations. When the compound is obtained from a carbon acid with a pKa ranging from about 15 to about 20, vascular relaxing effect is obtained at nanomolar concentrations without glutathione. The compound is preferably water-soluble and preferably contains a carbon alpha to the nitrosylated carbon which is part of a ketone group. In one embodiment, the C-nitroso compound is obtained by nitrosylation of a conventional drug or such drug modified to modify the carbon acid pKa thereof When such drug is a nonsteroidal anti-inflammatory drug, the resulting C-nitroso compound functions as a COX-1 and COX-2 inhibitor without the deleterious effects associated with COX-1 inhibition but with the advantageous effects associated with COX-1 and COX-2 inhibition. One such C-nitroso compound is a nitrosoketoibuprofen. A specific example of this kind of compound is isolated as dimeric 2-[4′-(α-nitroso)isobutyrylphenyl] propionic acid. In another case, the C-nitroso compound contains the moiety where X is S, O or NR One embodiment is directed to COX-2 inhibitors where a tertiary carbon atom and/or an oxygen atom and/or a sulfur atom is nitrosylated.
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Page column 61
(2010/11/29)
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- Lipase-catalyzed resolution of ibuprofen
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The resolution of ibuprofen by transesterification of its corresponding vinylester using lipase B from Candida antarctica is described. Compared to transesterification or hydrolysis of the ibuprofen ethyl ester (E2, 28-48h), the reaction with vinylesters occurred significantly faster (1.5-5h) and with considerably higher enantioselectivity (E=8-39).
- Henke, Erik,Schuster, Sascha,Yang, Hong,Bornscheuer, Uwe T.
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p. 633 - 638
(2007/10/03)
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- Isoxazole derivatives
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An isoxazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof useful as a therapeutic drug for auto-immune diseases and inflammatory diseases.
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- Catalytic process for preparing the alkyl esters of ibuprofen
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A process for preparing alkyl esters of ibuprofen is provided. A 1-halo-1-(4-isobutylphenyl)ethane is reacted in an anhydrous medium with carbon monoxide in the presence of an alkoxide source at a temperature between about 10° C. and about 200° C. An excess of several moles of alcohol is preferred. An acid such as hydrogen chloride may also be added. As catalyst, a palladium compound having at least one acid-stable ligand is present; however, an excess of ligand over palladium is advantageous.
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- Effect of group substitution on the physiochemical properties of ibuprofen prodrugs
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A series of alkyl ester prodrugs of ibuprofen was synthesized and studied for its physicochemical properties like aqueous solubility, octanol-water partition coefficient and hydrolysis kinetics in aqueous buffer and human plasma. These physicochemical parameters have a forebearing on the overall activity profile of these prodrugs. Mathematical relationships have been derived to characterize these properties.
- Bansal,Khar,Dubey,Sharma
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p. 422 - 424
(2007/10/02)
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- Comparison of the enzymatic activity of commercial and semipurified lipase of Candida cylindracea in the hydrolysis of the esters of (R,S) 2-aryl propionic acids
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A semipurified lipase of Candida cylindradea (LS) - easily obtained from commercial crude lipase (LC) - is used in the enantioselective hydrolysis of (R,S) 2-arylpropionates. The semipurification treatment diminishes the lipase activity more than the esterase activity. The addition of lactose (24 h) increases both activities. LS is more active than LC - at the same amount of protein - in the hydrolysis of (R,S) 2-aryl propionates. This semipurification showed a remarkable improvement in yield in the enantioespecific hydrolysis of these esters.
- Hernaiz, Maria J.,Sanchez-Montero, Jose M.,Sinisterra, Jose V.
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p. 10749 - 10760
(2007/10/02)
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- Thallium(III) Nitrate-mediated Efficient Synthesis of 2-Arylpropionic Acids from 1-Halogenoethyl Aryl Ketones
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Treatment of 1-halogenoethyl aryl ketones (1; R = H, iBu, OMe, Me, Ph, or Br; X = Br or Cl) with Tl(NO3)3*3H2O and perchloric acid in a trialkyl orthoformate at 25-50 deg C affords alkyl esters (3) of 2-arylpropionic acid in good-to-excellent yields via 1,2-aryl migration in substrates (1).The hydrolysis of esters (3) leads to the corresponding acids, some of which are pharmaceutically important compounds.The reaction hardly occurs in methanol.The key step of the reaction is the in situ acetal formation of the starting ketone.The thallium(III) salt acts as an effective Lewis acid catalyst for both acetal formation and halide abstraction.
- Yamauchi, Takayoshi,Nakao, Kenji,Fujii, Kyoichi
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p. 1255 - 1258
(2007/10/02)
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- Oxidative Rearrangement of Aryl Ethyl Ketones to Alkyl 2-Arylpropanoates by Lead(IV) Acetate
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Treatment of the propiophenones p-R'C6H4COCH2Me (1; R' = H, Me, Bui, Ph, Br) with lead(IV) acetate in trialkyl orthoformate in the presence of acid catalyst is found to give alkyl esters of 2-arylpropanoic acids (2) in good to excellent yields via 1,2-aryl migration in (1).Hydrolysis of (2) leads to the corresponding acids, some of which are important pharmaceutical compounds.The rate of aryl migration increases when the substituent R' is an electron-releasing group such as methyl, isobutyl, or phenyl.The rate of rearrangement of the dimethyl acetals of (1); R' = H, Bui, Ph) is nearly the same as that of (1).Such rearrangement hardly occurs in the absence of acid catalyst.A reaction pathway involving the formation of a monoalkoxylead(IV) compound, and its decomposition accompanied with aryl migration is discussed.
- Yamauchi, Takayoshi,Nakao, Kenji,Fujii, Kyoichi
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p. 1433 - 1436
(2007/10/02)
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- A NEW CONVENIENT SYNTHESIS OF α-ARYLPROPIONIC ACID ESTERS AND α-ARYLPROPIONITRILES
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Various types of α-arylpropionic acid esters were effectively obtained by the coupling reaction of aryl Grignard reagents and α-bromopropionic acid esters in the presence of nickel catalysts. α-Arylpropionitriles, precursors of α-arylpropionic acids, were also synthesized by the reaction of α-methanesulfonyloxypropionitrile and arylcopper reagents prepared from equimolar amount of arylmagnesium halides and copper(I) bromide.
- Amano, Takehiro,Yoshikawa, Kensei,Sano, Tatsuhiko,Ohuchi, Yutaka,Shiono, Manzo,et al.
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p. 499 - 508
(2007/10/02)
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- Optically active 1-aromatic-group-substituted-1-alkanones and methods for their manufacture
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A manufacturing method is described for the preparation of optically active 1-aromatic-group-substituted-1-alkanones characterized in that an optically active alkane acid halide is allowed to react with an aromatic compound in the presence of a Lewis acid. The optically active 1-aromatic-group-substituted-1-alkanones are useful intermediates in the preparation of optically active alpha-arylalkanoic acids, which are useful as pharmaceutical, e.g. anti-inflammatory, analgesic and anti-pyretic, agents and as insecticidal agents.
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- Process for producing α-arylalkanoic acid ester
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A process for producing an α-arylalkanoic acid ester represented by the general formula STR1 wherein Ar represents an aryl group which may optionally be substituted, and R1 and R2, independently from each other, represent a lower alkyl group, which comprises reacting a Grignard reagent prepared from an aryl halide of the general formula wherein Ar is as defined above and X1 represents a halogen atom, and magnesium, with an α-haloalkanoic acid ester of the general formula STR2 wherein R1 and R2 are as defined above, and X2 represents a halogen atom, said reaction of the Grignard reagent with the α-haloalkanoic acid ester of general formula (III) being carried out in the presence of a nickel compound.
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