cas 22071-15-4, Ketoprofen | Articles data

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Ester Prodrugs of Ketoprofen: Synthesis, Hydrolysis Kinetics and Pharmacological Evaluation
The ester prodrugs of ketoprofen with various naturally available antioxidants; menthol, thymol, eugenol, guiacol, vanillin and sesamol have been synthesized by the dicyclohexyl carbodiimide (DCC) coupling method, purified and characterized by spectral data. Further, their, partition coefficients have been determined as well as, hydrolytic studies performed. The synthesized compounds are more lipophilic compared to the parent moieties and are stable in acidic environment, which is a prerequisite for their oral absorption. Under gastric as well as intestinal pH conditions these prodrugs showed variable susceptibility towards hydrolysis. The title compounds when evaluated for anti-inflammatory, analgesic activities and ulcerogenicity, showed improvement over the parent drug.
Dhokchawle,Tauro,Bhandari
p. 46 - 50
(2015)
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Cobalt-Catalyzed Deprotection of Allyl Carboxylic Esters Induced by Hydrogen Atom Transfer
A brief, efficient method has been developed for the removal of the allyl protecting group from allyl carboxylic esters using a Co(II)/TBHP/(Me2SiH)2O catalytic system. This facile strategy displays excellent chemoselectivity, functional group tolerance, and high yields. This transformation probably occurs through the hydrogen atom transfer process, and a Co(III)-six-membered cyclic intermediate is recommended.
Li, Nan,Gui, Yizhen,Chu, Mengqi,You, Mengdi,Qiu, Xiaohan,Liu, Hejia,Wang, Shiang,Deng, Meng,Ji, Baoming
supporting information
p. 8460 - 8464
(2021/11/13)

Ketoprofen intermediate as well as preparation method and application thereof
The invention relates to the field, of medicine synthesis, in particular to a ketoprofen intermediate and a preparation method and application. thereof to prepare the ketoprofen, reaction formula by sequentially performing an oxidation reaction, substitution reaction, deamination, deamination and an acidic hydrolysis reaction after formation of the isoxazole compound, by a Diels,Alder reaction with a phenylacetic acid by. a Diels :Alder reaction of a phenylacetic acid. In-flight, X2 or. Ortho or para, R to nitro or amino group1 - COCONR4 R5 , COX1 , COOR2 Or - CNCNCNR2 , R3 , R4 , R5 , R6 The same or different is H or C. 1 - C6 Alkyl, X1 , X2 The same or different is F, Cl, Br or I.
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Paragraph 0193-0195

(2020/03/12)

Preparation method of aryl propionic acid compound
The invention provides a preparation method of an aryl propionic acid compound, wherein the preparation method comprises the following steps: carrying out acetylation reaction on substituted aryl benzene to obtain aryl acetophenone; carrying out hydrogenation reduction reaction on alpha-substituted aryl ethyl ketone to obtain alpha-substituted aryl ethanol; and in an acidic solution, introducing carbon monoxide gas into the alpha-substituted aryl ethanol, and carrying out a carbonylation reaction under the co-catalytic action of a main catalyst and a cocatalyst to obtain the aryl propionic acid compound, wherein the cocatalyst has the following structural formula described in the specification, R1 is one of hydrogen and a substituted carboxylic acid group, and R2 is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 naphthenic base, substituted carbonyl containing C6-C24 aryl or substitutedaryl, substituted carbonyl containing C3-C12 heterocyclic radical or substituted heterocyclic radical, phenyl, substituted phenyl, naphthyl and substituted naphthyl.
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Page/Page column 0121-0125

(2020/10/04)

Ketoprofen intermediate as well as preparation method and application thereof
The invention relates to the field of medicine synthesis, in particular to a Ketoprofen intermediate as well as a preparation method and application thereof. Ketoprofen is prepared from p--nitrohalobenzene and o-nitrohalobenzene or a mixture of the p-nitrohalobenzene and the o-nitrohalobenzene as raw materials by first performing Diels-Alder reaction on the raw materials and phenylacetonitrile toobtain an isoxazole compound, and then sequentially carrying out oxidation reaction, substitution reaction, reduction reaction, deamination, ester removal and acid hydrolysis reaction to prepare the ketoprofen. The reaction formula is as shown in the specification, wherein X2 and a group as shown in the specification are located in ortho-position or para-position of a nitro group or an amino group, R1 is-CONR4R5,-COX1,-COOR2 or-CN, R2, R3, R4 and R5 are same or differently H or a C1-C6 alkyl group, and X1 and X2 are the same or different, and are F, Cl, Br Or I.
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Paragraph 0193-0195

(2019/05/02)

Palladium-Catalyzed α-Arylation of Carboxylic Acids and Secondary Amides via a Traceless Protecting Strategy
A novel traceless protecting strategy is presented for the long-standing challenge of conducting the palladium-catalyzed α-arylation of carboxylic aids and secondary amides with aryl halides. Both of the presented coupling processes occur with a variety of carboxylic acids and amides and with a variety of aryl bromides containing a broad range of functional groups, including base-sensitive functionality like acyl, alkoxycarbonyl, nitro, cyano, and even hydroxyl groups. Five commercial drugs were prepared through this method in one step in 81-96% yield. Gram-scale synthesis of medication Naproxen and Flurbiprofen with low palladium loading further highlights the practical value of this method.
He, Zhi-Tao,Hartwig, John F.
supporting information
p. 11749 - 11753
(2019/08/26)

Method for synthesizing dexketoprofen intermediate
The invention belongs to the technical field of medicines, and particularly relates to a method for synthesizing a dexketoprofen intermediate. The dexketoprofen intermediate is prepared by asymmetricsynthesis of Darzens reaction. The method can improve the selectivity of the reaction, reduce the loss of raw materials, improve the yield and simplify the operation process, and is conducive to industrial production.
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Paragraph 0036-0039

(2019/01/16)

A general approach to intermolecular carbonylation of arene C-H bonds to ketones through catalytic aroyl triflate formation
The development of metal-catalysed methods to functionalize inert C-H bonds has become a dominant research theme in the past decade as an approach to efficient synthesis. However, the incorporation of carbon monoxide into such reactions to form valuable ketones has to date proved a challenge, despite its potential as a straightforward and green alternative to Friedel-Crafts reactions. Here we describe a new approach to palladium-catalysed C-H bond functionalization in which carbon monoxide is used to drive the generation of high-energy electrophiles. This offers a method to couple the useful features of metal-catalysed C-H functionalization (stable and available reagents) and electrophilic acylations (broad scope and selectivity), and synthesize ketones simply from aryl iodides, CO and arenes. Notably, the reaction proceeds in an intermolecular fashion, without directing groups and at very low palladium-catalyst loadings. Mechanistic studies show that the reaction proceeds through the catalytic build-up of potent aroyl triflate electrophiles.
Kinney, R. Garrison,Tjutrins, Jevgenijs,Torres, Gerardo M.,Liu, Nina Jiabao,Kulkarni, Omkar,Arndtsen, Bruce A.
p. 193 - 199
(2018/02/06)

Ketoprofen preparation method
The invention provides a ketoprofen preparation method. The ketoprofen preparation method includes 1), taking phenacyl halide and acetanilide as raw materials, and subjecting the raw materials to Friedel-Crafts acylation to obtain 4-acetamido benzophenone; 2), subjecting the 4-acetamido benzophenone and 1, 2-dichloropropane to Friedel-Crafts acylation to obtain 2-(1-chloroisopropyl)-4-benzoyl acetanilide; 3), subjecting the 2-(1-chloroisopropyl)-4-benzoyl acetanilide to deprotection in an acidic condition to obtain 2-(1-chloroisopropyl)-4-benzoyl aniline; 4), subjecting the 2-(1-chloroisopropyl)-4-benzoyl aniline to alkali hydrolysis to obtain 2-(1-hydroxyisopropyl)-4-benzoyl aniline; 5), subjecting the 2-(1-hydroxyisopropyl)-4-benzoyl aniline to diazotization and reduction to compound 3-benzoyl-alpha-methyl phenylethanol; 6), oxidizing the 3-benzoyl-alpha-methyl phenylethanol to obtain ketoprofen. The ketoprofen preparation method has the advantages of non-existence of dangerous reaction process and high yield.
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Paragraph 0044-0046

(2017/07/01)

Preparation method of ketoprofen
The invention discloses a preparation method of ketoprofen. The method takes m-bromobenzoic acid and benzene as starting raw materials, and the ketoprofen is prepared through the steps of acylating, protecting a carbonyl group, taking a Grignard reagent, reacting with propylene oxide, oxidizing, de-protecting and the like. The method disclosed by the invention has the characteristics of short reaction route, easiness of obtaining the raw materials, high yield and low cost.
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(2017/07/14)

Preparation process of ketoprofen
The invention discloses a preparation process of ketoprofen. A method takes benzoyl chloride and acetanilide as starting raw materials, and the ketoprofen is prepared through the steps of acylating, carting out acylation, de-protecting, hydrolyzing, carrying out diazotization reduction, carrying out Darzens reaction, oxidizing and the like. According to the method disclosed by the invention, the raw materials have cheap prices and are easy to obtain; the process is easy to realize and a hazardous process does not exist in the reaction; the yield is high and reaction conditions are moderate; the preparation method is simple and convenient to operate and has low requirements on equipment.
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(2017/07/19)

Chemoselective Transformation of Diarylethanones to Arylmethanoic Acids and Diarylmethanones and Mechanistic Insights
The chemoselective transformation of diarylethanones via either aerobic oxidative cleavage to give arylmethanoic acids or tandem aerobic oxidation/benzilic acid rearrangement/decarboxylation to give diarylmethanones has been developed. The transformation is controllable and applicable to a broad spectrum of substrates and affords the desired products in good to excellent yields. Mechanistic insights with control reactions, 1H NMR tracking, and single-crystal X-ray diffraction reveal a complex mechanistic network in which two common intermediates, α-ketohydroperoxide and diarylethanedione, and three plausible pathways are proposed and verified. These pathways are interlinked and can be switched reasonably by changing the reaction conditions. This method enables scalable synthesis and access to a number of valuable compounds, including vitamin B3, diphenic acid, and the nonsteroidal anti-inflammatory drug ketoprofen. The present protocol represents a step forward in exploiting complex mechanistic networks to control reaction pathways, achieving divergent syntheses from the same class of starting materials.
Wang, Xing,Chen, Rui-Xi,Wei, Zeng-Feng,Zhang, Chen-Yang,Tu, Hai-Yang,Zhang, Ai-Dong
p. 238 - 249
(2016/01/15)

Carbonylative coupling of aryl tosylates/triflates with arylboronic acids under CO atmosphere
The carbonylative Suzuki-Miyaura reaction between aryl tosylates/triflates with arylboronic acid is herein reported, using base-free conditions and a balloon pressure of carbon monoxide. Under these conditions, unsymmetrical biaryl ketones were obtained in modest to excellent yields. This method was adapted to the synthesis of oxybenzone and ketoprofen in good yields under mild conditions.
Hao, Cheng Yi,Wang, Dan,Li, Ya Wei,Dong, Lin Lin,Jin, Ying,Zhang, Xiu Rong,Zhu, He Yun,Chang, Sheng
p. 86502 - 86509
(2016/09/23)

COMPOSITIONS AND METHODS FOR THE TREATMENT OF MODERATE TO SEVERE PAIN
The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II, and methods for treating or preventing or modulating moderate to severe pain in a disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder.
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Paragraph 0121; 0128; 0129

(2015/05/26)

COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION
The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of inflammation may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of Type II diabetes, Type I diabetes, insulin resistance, cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, macular adema, arthritis, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome, neudegeneration, Alzheimer's disease, Huntington's disease, Ulcerative colitis, Crohn's disease, Multiple Sclerosis, muscular dystropthy, metabolic syndrome, fatty liver, bone diseases, inflammatory diseases.
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Paragraph 0112; 0119; 0120

(2015/06/03)

METHOD FOR PRODUCING PULVERIZED ORGANIC COMPOUND PARTICLE
Disclosed is a method for producing pulverized particles of a crystalline organic compound which is poorly water-soluble. Also disclosed is a pulverized organic compound particle produced by such a method. Specifically disclosed is a method for producing a poorly water-soluble organic compound particle for medical use, which is characterized in that a poorly water-soluble organic compound for medical use is mixed with a physiologically acceptable salt and a physiologically acceptable polyol, and subjected to wet milling. Also specifically disclosed is a poorly water-soluble organic compound particle for medical use, which is produced by such a production method.
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(2015/12/19)

Laccase-Mediator System for Alcohol Oxidation to Carbonyls or Carboxylic Acids: Toward a Sustainable Synthesis of Profens
By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration.
Galletti, Paola,Pori, Matteo,Funiciello, Federica,Soldati, Roberto,Ballardini, Alberto,Giacomini, Daria
p. 2684 - 2689
(2016/12/23)

One-pot synthesis of diarylmethanones through palladium-catalyzed sequential coupling and aerobic oxidation of aryl bromides with acetophenone as a latent carbonyl donor
A one-pot palladium-catalyzed synthesis of symmetrical and unsymmetrical diarylmethanones using acetophenone and aryl bromides as raw materials has been developed. In this reaction, acetophenone acts as a latent carbonyl donor and two pathways of palladium-catalyzed sequential coupling and aerobic oxidation are identified. The reaction is applicable to a spectrum of substrates and delivers the products in moderate to good yields. This method can be used for the synthesis of ketoprofen, a nonsteroidal anti-inflammatory drug, in a two-step procedure and 45% overall yield.
Wang, Xing,Liu, Fu-Di,Tu, Hai-Yang,Zhang, Ai-Dong
p. 6554 - 6562
(2014/08/05)

COMPOSITIONS AND METHODS FOR THE TREATMENT OF MODERATE TO SEVERE PAIN
The invention relates to the compounds of formula (I) and formula (II) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I) or formula (II), and methods for treating or preventing or modulating moderate to severe pain in a disease may be formulated for oral buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder.
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Paragraph 0097; 00104; 00105

(2013/12/03)

COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION
The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of inflammation may he formulated for oral buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of Type II diabetes, Type I diabetes, insulin resistance, cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, macular adema, arthritis, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome, neudegeneration, Alzheimer's disease, Huntington's disease. Ulcerative colitis, Crohn's disease. Multiple Sclerosis, muscular dystropthy, metabolic syndrome, fatty liver, bone diseases, inflammatory diseases.
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Paragraph 0094; 00101; 00102

(2013/12/03)

Laboratory evolution of enantiocomplementary Candida antarctica lipase B mutants with broad substrate scope
Candida antarctica lipase B (CALB) is a robust and easily expressed enzyme used widely in academic and industrial laboratories with many different kinds of applications. In fine chemicals production, examples include acylating kinetic resolution of racemic secondary alcohols and amines as well as desymmetrization of prochiral diols (or the reverse hydrolytic reactions). However, in the case of hydrolytic kinetic resolution of esters or esterifying kinetic resolution of acids in which chirality resides in the carboxylic acid part of the substrate, rate and stereoselectivity are generally poor. In the present study, directed evolution based on iterative saturation mutagenesis was applied to solve the latter problem. Mutants with highly improved activity and enantioselectivity relative to wild-type CALB were evolved for the hydrolytic kinetic resolution of p-nitrophenyl 2-phenylpropanoate, with the selectivity factor increasing from E = 1.2 (S) to E = 72 (S) or reverting to E = 42 (R) on an optional basis. Surprisingly, point mutations both in the acyl and alcohol pockets of CALB proved to be necessary. Some of the evolved CALB mutants are also efficient biocatalysts in the kinetic resolution of other chiral esters without performing new mutagenesis experiments. Another noteworthy result concerns the finding that enantiocomplementary CALB mutants for α-substituted carboxylic acid esters also show stereocomplementarity in the hydrolytic kinetic resolution of esters derived from chiral secondary alcohols. Insight into the source of stereoselectivity was gained by molecular dynamics simulations and docking experiments.
Wu, Qi,Soni, Pankaj,Reetz, Manfred T.
supporting information
p. 1872 - 1881
(2013/08/24)

One-step oxidation of 2-arylpropanols to 2-arylpropionic acids: Improving sustainability in the synthesis of profens
Three oxidation procedures were evaluated for the synthesis of optically pure 2-arylpropionic acids. Efficient, mild, and eco-friendly conditions were obtained with the system comprising TEMPO, NaClO, and NaClO2. Thus a series of profens were obtained in good to excellent yields. Georg Thieme Verlag Stuttgart New York.
Galletti, Paola,Pori, Matteo,Giacomini, Daria
experimental part
p. 2644 - 2648
(2010/11/18)

Catalytic asymmetric synthesis using feedstocks: An enantioselective route to 2-arylpropionic acids and 1-arylethyl amines via hydrovinylation of vinyl arenes
A three-step procedure for the synthesis of 2-arylpropionic acids (profens) from vinyl arenes in nearly enantiomerically pure form has been developed. Excellent yields (>97%), regioselectivities (>99%), and enantioselectivities (>97% ee) for the desired branched products were obtained in the asymmetric hydrovinylation reactions of vinyl arenes, and the products from these reactions were transformed into 2-arylpropionic acids via oxidative degradation. Subsequent Curtius or Schmidt rearrangements of these acids provided highly valued 1-arylethyl amines, including a prototypical primary amine with an α-chiral tertiary N-alkyl group, in very good yields.
Smith, Craig R.,Babu, T.V. Rajan
experimental part
p. 3066 - 3072
(2009/08/08)

An efficient and practical sequential one-pot synthesis of suprofen, ketoprofen and other 2-arylpropionic acids
A novel sequential double carbonylation to synthesize anti-inflammatory drugs such as Ketoprofen and Suprofen has been developed. Starting from easily available aryl halides and arylboronic acids a one-pot carbonylative Suzuki and hydroxycarbonylation reaction sequence proceeds in good selectivity and high yield in the presence of the palladium/cataCXium A catalyst system. Applying optimized conditions different 2-arylpropionic acids were synthesized in good yields.
Neumann, Helfried,Brennfuehrer, Anne,Beller, Matthias
experimental part
p. 2437 - 2442
(2009/10/06)

Expanding the substrate scope of enzymes: Combining mutations obtained by CASTing
In a previous paper, the combinatorial active-site saturation test (CAST) was introduced as an effective strategy for the directed evolution of enzymes toward broader substrate acceptance. CASTing comprises the systematic design and screening of focused libraries around the complete binding pocket, but it is only the first step of an evolutionary process because only the initial libraries of mutants are considered. In the present study, a simple method is presented for further optimization of initial hits by combining the mutational changes obtained from two different libraries. Combined lipase mutants were screened for hydrolytic activity against six notoriously difficult substrates (bulky carboxylic acid esters) and improved mutants showing significantly higher activity were identified. The enantioselectivity of the mutants in the hydrolytic kinetic resolution of two substrates was also studied, with the best mutant-substrate combination resulting in a selectivity factor of E=49. Finally, the catalytic profile of the evolved mutants in the hydrolysis of simple nonbranched carboxylic acid esters, ranging from acetate to palmitate, was studied for theoretical reasons.
Reetz, Manfred T.,Carballeira, Jose Daniel,Peyralans, Jerome,Hoebenreich, Horst,Maichele, Andrea,Vogel, Andreas
p. 6031 - 6038
(2007/10/03)

A PROCESS FOR THE PREPARATION OF ALPHA-ARYLALKANOIC ACIDS
A process for the preparation of meta or para-substituted alpha-arylalkanoic acids of formula (I)wherein R and R1 are as defined in the disclosure.
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(2008/06/13)

An interesting synthetic application of S-alkyl (aryl)bis(alkylsulfanyl)thioacetates: General procedure for the preparation of (±)-α-arylpropionic acids
Reported here is a new procedure for the synthesis of α-arylpropionic acids 1 in the racemic form, starting from derivatives of aromatic carboxylic acids 2 (i.e., esters), via 1-aryl-2,2,2-tris(alkylsulfanyl)ethanones 4-6, S-alkyl (aryl)bis(alkylsulfanyl)thioacetates 7-9, S-alkyl α-aryl-α-(alkylsulfanyl)thiopropionates 10-12 and S-alkyl α-arylthiopropionates 13-15. Each stage takes place easily and yields are always high.
Clericuzio, Marco,Degani, Iacopo,Dughera, Stefano,Fochi, Rita
p. 921 - 927
(2007/10/03)

1-Ethyl and 1-propylazacycloalkan-2-one ester prodrugs of ketoprofen: Synthesis, chemical stability, enzymatic hydrolysis, anti-inflammatory activity, and gastrointestinal toxicity
Six ketoprofen (CAS 22071-15-4) alkylazacycloalkan-2-one ester derivatives (I-VI) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities after oral administration. Furthermore these derivatives were assayed to determine in vitro their stability in pH 7.4 phosphate buffer and in simulated gastric fluid (pH 2.0 buffer) and their susceptibility to enzymatic cleavage in rat plasma. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by rat plasma. Esters I-VI showed an anti-inflammatory activity, determined as the percent of inhibition of carrageenan-induced edema, similar to that of ketoprofen, although at higher doses. They were significantly less irritating to the gastric mucosa than the parent drug. In the mouse acetic acid induced writhing assay, the prodrugs exhibited, following acute administration, a good analgesic activity.
Bonina, Francesco Paolo,Puglia, Carmelo,Ventura, Dario,Santagati, Natale Alfredo,Saija, Antonella,Trombetta, Domenico
p. 884 - 889
(2007/10/03)

Synthesis of a new insoluble polymer-supported chiral alcohol auxiliary and its first application to nucleophilic addition to ketenes
The preparation of a new optically active alcohol with a carboxylic function that allowed its attachment to an amine-functionalized insoluble polymer is described. Its first use as a polymer supported chiral auxiliary is demonstrated by asymmetric transformation of two racemic aryl propionic acids via ketene formation (95-96% ee).
Akkari,Calmes,Mai,Rolland,Martinez
p. 5859 - 5865
(2007/10/03)

Preparation of carboxylic compounds and their derivatives
Palladium-catalyzed arylation of an olefin (e.g., ethylene) with an aromatic halide (e.g., 2-bromo-6-methoxynaphthalene, m-bromobenzophenone, or 4-isobutyl-1-bromobenzene) is conducted in specified media. After a special acid or base phase separation procedure, palladium-catalyzed carbonylation of the olefinically-substituted aromatic intermediate is conducted in specified media using CO and water or an alcohol to form arylalkylcarboxylic acid or ester or substituted arylalkylcarboxylic acid or ester (e.g., racemic 2-(6-methoxy-2-naphthyl)propionic acid, 2-(3-benzoylphenyl)propionic acid, or 2-(4-isobutylphenyl)propionic acid). Catalyst recovery procedures enabling recycle of catalyst residues and efficient recovery of amine hydrogen halide scavenger and solvent used in the arylation reaction are described, as well as novel, highly efficient methods of conducting the carbonylation reaction. The technology is economical and suitable for use on an industrial scale whereby reaction mixtures can be efficiently separated into the desired component mixtures without need for excessive capital investment or tedious, time-consuming operations. High yields of high purity products can be achieved.
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(2008/06/13)

Sol-controlled thermocolloid matrix based on gelatin for oral sustained-release form
A peroral depot medicament with controlled active substance release is composed of a gelatine matrix that continuously dissolves in an aqueous medium above 37° C., and a medicament distributed therein. The release of the medicament, that may be easily or scarcely soluble, lipophilic or hydrophilic, is variable in time and may be adjusted according to the medicament.
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(2008/06/13)

Studies on anti-inflammatory drugs of 2-arylpropanoic acids: Part IX - A practical synthesis of ketoprofen by 1,2-aryl rearrangement
An efficient synthesis of ketoprofen via chloration, Friedel-Crafts acylation, reduction, coupling, ketalization, rearrangement, hydrolysis and oxidation from commercially available m-bromo-benzoic acid in overall yield of about 60% has been described.
Chen, Fener,Liu, Jidong,Shao, Lanying,Yan, Qiongjiao
p. 989 - 992
(2007/10/03)

In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen
A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log P(app)). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the patent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.
Rautio, Jarkko
p. 1622 - 1628
(2007/10/03)

Prodrugs: Part 3. 2-Formylphenyl esters of indomethacin, ketoprofen and ibuprofen and 6-substituted 2-formyl and 2-acylphenyl esters of aspirin
The synthesis and study of a novel series of potential prodrugs of indomethacin, ketoprofen, ibuprofen and aspirin are reported. 2-Formylphenyl esters of the NSAIDs, together with two 6-substituted 2-formyl and two 2-acylphenyl aspirins and 4-formylphenyl indomethacin, have been prepared. A study of their alkaline and neutral hydrolysis shows that these compounds, with the exception of 2-acetylphenyl aspirin, act as true prodrugs of the NSAIDs, giving the NSAID and acylphenol. The rates of hydrolysis and activation parameters indicate that the 2-acylphenyl esters employ an intramolecular catalytic route. The 2-formylphenyl esters were more potent as anti-inflammatory agents than the parent compounds in the carragheenan-induced paw oedema test.
Abordo, Evelyn A.,Bowden, Keith,Huntington, Anthony P.,Powell, Sarah L.
p. 95 - 101
(2007/10/03)

Process for optically resolving 2-(3-benzoylphenyl) propionic acid
Provided is a process for separating (S)- or (R)-2-(3-benzoylphenyl)propionic acid from a mixture of (S)- and (R)-2-(3-benzoylphenyl)propionic acid, which comprises (1) reacting the mixture of (S)- and (R)-2-(3-benzoylphenyl)propionic acid with (S)- or (R)-3-methyl-2-phenylbutylamine in a suitable solvent to form a diastereomer salt of (S)-2-(3-benzoylphenyl)propionic acid with (S)-3-methyl-2-phenylbutylamine or a diastereomer salt of (R)-2-(3-benzoylphenyl)propionic acid with (R)-3-methyl-2-phenylbutylamine; (2) separating the diastereomer salt from the reaction mixture; and (3) liberating the separated diastereomer salt to give (S)- or (R)-2-(3-benzoylphenyl)propionic acid. According to the present process, it is possible to obtain optically active (S)- or (R)-2-(3-benzoylphenyl)propionic acid having 99% or more of high optical purity in a high yield. Thus, the present process is a practical and efficient process which can simplify purification steps and can be applied for an industrial production process.
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(2008/06/13)

Bisphosphines for asymmetric hydrogenation catalysts
The invention relates to novel enantiomerically pure bisphosphines of the general formula (I) STR1 in which R, R1 and R2 have the meanings given in the description, a process for the preparation thereof and the use thereof in metal complexes as catalysts for asymmetric hydrogenations.
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(2008/06/13)

Enantioselective syntheses of 2-arylpropanoic acid non-steroidal antiinflammatory drugs and related compounds
(S)-2-[4′-(2″-Methylpropyl)phenylpropanoic acid (ibuprofen) and (S)-2-(3′-benzoylphenyl)propanoic acid (ketoprofen) have been synthesised in high enantiomeric excess. Control of stereochemistry was achieved by a combination of Sharpless epoxidalion followed by catalytic hydrogenolysis of the introduced benzylic epoxide oxygen bond. Also, the coupling of organic compounds in the presence of palladium with enantiopure 2-(3-iodophenyl)propanoic and 2-(4-iodophenyl)propanoic acids, prepared by the methodology above, is a general method for the synthesis of optically active arylpropanoic acids.
Hamon, David P.G.,Massy-Westropp, Ralph A.,Newton, Josephine L.
p. 12645 - 12660
(2007/10/02)

Alternative synthesis of 2-arylpropanoic acids from enolate and aryl halides
Arylpropanoic acids, a type of non-steroidal antiinflammatory drug, have been prepared in liquid ammonia by photo-radical nucleophilic substitution of halogenoarenes with sodium N,N-dimethylacetamide enolate followed by methylation and hydrolysis.Rapid substitution occured in many cases with good to excellent yields of arylpropanoic acids.The title compounds have also been prepared by arylation of sodium acetone enolate with methylation and oxidation in a haloform reaction.
Ferrayoli, Carlos G.,Palacios, Sara M.,Alonso, Ruben A.
p. 1635 - 1638
(2007/10/02)

A comparative study on the photo-induced arylation of β-dicarbonyl compounds by arylazosulfides and its use in the synthesis of methyl labeled 2-arylpropionic acids
A comparative study on the arylation of β-dicarbonyl derivatives (acetylacetone, methyl acetoacetate and dimethyl malonate) by using the photo-induced decomposition of arylazosulfides is presented. The arylazosulfides used contained the aryl moieties related to Ketoprofen or Ibuprofen and the reaction was performed following the procedure reported by Dell'Erba et al. (Tetrahedron, 1991, 47, 333). From the arylazosulfides assayed, only those bearing a carbonyl group attached to the benzene ring, i.e. 1 and 11, afforded the corresponding arylation adducts in satisfactory yields. Concerning the β-dicarbonyl derivatives, condensation of acetylacetone in the case of 1 and of dimethyl malonate in that of 11 gave the best results. However, the further methylation of the aryl β-dicarbonyl adduct was clearly advantageous for the case of the 2-arylmalonate derivatives. The use of this synthetic strategy for the convenient preparation of Ketoprofen (23% overall yield, 7 steps from 3-nitrobenzophenone) and Ibuprofen (34% overall yield, 8 steps from 4-isobutyrylbenzene) isotopomers labeled at the methyl group at C-2 is also reported.
Tona, Merce,Sanchez-Baeza, Francisco,Messeguer, Angel
p. 8117 - 8126
(2007/10/02)

Process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and arylacetic acids
A process for the α-monoalkylation of arylacetonitriles, arylacetoesters and arylacetic acids with dialkyl carbonates in liquid phase, in the presence of bases at temperatures ranging from about 100° C. to about 270° C.
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(2008/06/13)

Gastric preparation with sustained release
A gastric preparation developed in order to solve the technical problems of conventional preparations, which is prepared by the bilayer packing technique and comprises 5 to 60%, desirably 10 to 40% of a rapid release portion which can establish the therapeutic level of a drug shortly after the administration and 95 to 40%, desirably 90 to 60% of a sustained release portion which has a specific gravity or 1 or less and can maintain a satisfactory release rate.
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(2008/06/13)

Photochemical Rearrangement of α-Chloro-Propiophenones to α-Arylpropanoic Acids: Studies on Chirality Transfer and Synthesis of (S)-(+)-Ibuprofen and (S)-(+)-Ketoprofen
A new single-step efficient photochemical approach for α-arylpropanoic acids (4) from α-chloro-propiophenones (5) is described.It involves carbonyl triplet excited state directed 1,2-aryl migration of the aryl group which has been found to be highly dependent upon the nature of the aryl substituent.The mode of the rearrangement is probed by the study of the photobehaviour of a set of optically active α-chloro-propiophenones.The results suggest that the nature of the carbonyl triplets (n, ?*/ ?, ?*) plays an important role in the chirality transfer.This method finds application in the synthesis of optically active ibuprofen (4e) and ketoprofen (26), though in moderate optical yields.
Sonawane, Harikisan,Bellur, Nanjundiah S.,Kulkarni, Dilip G.,Ayyangar, Nagaraj R.
p. 1243 - 1260
(2007/10/02)

A process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and arylacetic acids
A process for the α-monoalkylation of arylacetonitriles, arylacetoesters and arylacetic acids with dialkyl carbonates in liquid phase, in the presence of bases at temperatures ranging from about 100°C to about 270°C.
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(2008/06/13)

A NEW METHOD OF SYNTHESIS OF α-ARYLPROPIONIC ACIDS INVOLVING COPPER(I) HOMOGENEOUS CATALYSIS
The synthesis of α-arylpropionic acids involving, as first step, the facile coupling af an aryl bromide and diethyl malonate in the presence of Cu(I) bromide is described.The limits of application are discussed.
Ugo, Renato,Nardi, Paola,Psaro, Rinaldo,Roberto, Dominique
p. 511 - 514
(2007/10/02)

Production of α-(3-benzoylphenyl)propionic acid derivative
This invention provides a method of producing highly pure α-(3-benzoylphenyl)propionic acid derivatives, which are medicines per sec or which can easily afford the same, from readily available 3-ethylbenzophenone in a very simplified manner efficiently and economically. The method comprises dehydrogenating 3-ethylbenzophenone in vapor phase in the presence of an inert gas and carbonylating the formed 3-ethenylbenzophenone in the presence of a carbonylation catalyst comprising a transition metal complex.
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(2008/06/13)

1-(3-Vinylphenyl)-1-phenyl-hydrocarbons and method for producing the same
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(2008/06/13)

DIRECT, REGIOSELECTIVE HYDROCARBOXYLATION OF ALKYNES TO SATURATED ACIDS BY COBALT AND NICKEL CATALYSTS UNDER PHASE TRANSFER CONDITIONS
Phase transfer catalyzed carbonylation of alkynes in the presence of cobalt chloride, potassium cyanide, and nickel cyanide affords saturated carboxylic acids, with good selectivity observed for the branched-chain isomer.
Lee, Jong-Tae,Alper, Howard
p. 1769 - 1770
(2007/10/02)

(Vinylphenyl)phenylmethane and method for producing (benzoylphenyl)propionic acid
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(2008/06/13)

Process for preparing alpha-(3-benzylphenyl) propionic acid derivative
A process for preparing α-(3-benzylphenyl)-propionic acid or its derivative, a precursor of ketoprofen (trade name), which comprises dehydrogenating a by-product oil fraction formed in the production of ethylbenzene using synthetic zeolite as an alkylating catalyst, and carbonylating the product with carbon monoxide or the like. This precursor can be easily converted into ketoprofen, a useful medicine as an anti-inflammatory agent.
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(2008/06/13)

Prodrug derivatives of carboxylic acid drugs
Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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(2008/06/13)