- Preparation method of flurbiprofen
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The invention relates to a preparation method of flurbiprofen. The method comprises the following steps: (1) reacting 2-fluoro-4-brominated biphenyl with metal magnesium at the temperature of 40-65 DEG C to prepare (2-fluorine-[1,1'-biphenyl]-4-yl) magnesium bromide; (2) reacting (2-fluorine-[1,1'-biphenyl]-4-yl) magnesium bromide and ethyl 2-bromopropionate under the action of a nickel catalyst to prepare flurbiprofen ethyl ester; (3) hydrolyzing the flurbiprofen ethyl ester to prepare the flurbiprofen sodium; and (4) dissolving flurbiprofen sodium in water, adding acid to adjust the pH value, and separating out flurbiprofen. According to the preparation method, use of high-risk reagents is avoided, and used chemical reagents are cheap and easy to obtain; the preparation method has the advantages of being simple and convenient to operate, safe, controllable, good in reproducibility, high in product yield, high in purity, safe, environmentally friendly, low in cost, and suitable for industrial production and the like.
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Paragraph 0050-0061
(2021/05/12)
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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.
- Liu, Xiaolong,Zhao, Meng,Fan, Xinjiong,Fu, Yao
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p. 6126 - 6133
(2021/09/28)
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- LiCl-Accelerated multimetallic cross-coupling of aryl chlorides with aryl triflates
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While the synthesis of biaryls has advanced rapidly in the past decades, cross-Ullman couplings of aryl chlorides, the most abundant aryl electrophiles, have remained elusive. Reported here is the first general cross-Ullman coupling of aryl chlorides with aryl triflates. The selectivity challenge associated with coupling an inert electrophile with a reactive one is overcome using a multimetallic strategy with the appropriate choice of additive. Studies demonstrate that LiCl is essential for effective cross-coupling by accelerating the reduction of Ni(II) to Ni(0) and counteracting autoinhibition of reduction at Zn(0) by Zn(II) salts. The modified conditions tolerate a variety of functional groups on either coupling partner (42 examples), and examples include a three-step synthesis of flurbiprofen.
- Huang, Liangbin,Ackerman, Laura K. G.,Kang, Kai,Parsons, Astrid M.,Weix, Daniel J.
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p. 10978 - 10983
(2019/08/07)
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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
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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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- Preparation method of flurbiprofen and preparation method of flurbiprofen axetil
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The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of flurbiprofen and a preparation method of flurbiprofen axetil. The preparation method of the flurbiprofen comprises the steps of carrying out a Grignard reaction by using 4-bromine-2-fluorine biphenyl as a raw material, carrying out a coupling reaction, and acidizing to obtain the flurbiprofen; the yield is 90%, and the purity is 99.5%; then, the flurbiprofen axetil is prepared by using the flurbiprofen, obtained by the method, as a raw material, the yield reaches up to 90%, and thepurity reaches up to 99.5%. The preparation methods are high in quality controllability and industrial reproducibility.
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Paragraph 0007; 0029; 0044
(2018/10/19)
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- Preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid
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The invention discloses a preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid, and belongs to the technical fields of chemical synthesis and medicines. A zinc reagent is prepared from trimethyl-chlorosilane as a zinc powder activating agent; with 4-bromo-2-fluoro biphenyl as a raw material, 2-(2-fluoro-4-biphenyl) ethyl propionate is obtained by reaction under the action of the zinc reagent and a catalyst-ligand; and the 2-(2-fluoro-4-biphenylyl) propionic acid is obtained through hydrolysis. The method is simple in process, simple and convenient to operate and short in reaction time; the product is high in yield, few in impurity, simple in post-treatment, high in equipment utilization rate and suitable for large-scale industrial production and application. Particularly, by a metal nickel-ligand catalyst system, the catalyst is high in activity and low in dosage; and the yield of the product can be effectively improved.
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Paragraph 0027; 0030; 0062; 0063; 0064; 0065; 0066; 0067
(2016/11/02)
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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)
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- Ester prodrugs of flurbiprofen: Synthesis, plasma hydrolysis and gastrointestinal toxicity
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Nine alkyl ester prodrugs of flurbiprofen have been synthesized with an aim to reduce it's gastrointestinal side-effects. The synthesized prodrugs have been subjected to plasma hydrolysis and gastrointestinal toxicity studies. The chemical structures of t
- Mohan, Rhea,Ramaa
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p. 1164 - 1168
(2008/09/19)
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- Regio- and stereoselective hydrogenolysis of optically active diols via transfer hydrogenation : Synthesis of α- arylpropionic acids
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Asymmetric synthesis of α-arylpropionic acids, Ibuprofen 1b, Naproxen 1c, and Flurbiprofen 1d have been achieved by employing Sharpless asymmetric dihydroxylation followed by the stereoselective hydrogenolysis of the chiral diols coupled with Jones' oxidation as the key steps. The regio- and stereoselective hydrogenolysis of the chiral diols at the benzylic position proceeds with retention of configuration for all the substrates studied.
- Nandanan,Jayachandran,Phukan, Prodeep,Pais, Godwin C. G.,Sudalai
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p. 1221 - 1227
(2007/10/03)
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- Aminoazole derivatives and their production and use
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A compound of the formula: STR1 wherein A is the group of the formula: wherein Ar1 is a phenyl or thienyl group which may be optionally substituted with at least one of the same or different halogen atom; Ar2 is a phenylene or thienylene group which may be optionally substituted with at least one of the same or different halogen atom; D is a divalent radical selected from the group consisting of >C=N--OR4 [wherein R4 is a hydrogen atom or lower alkyl group], >C=O, STR2 >CHOH, >NH radical, or single bond, STR3 wherein R5 is a lower alkoxy or a phenyl group which may be optionally substituted with at least one of the same or different halogen atom; E is a methine group or a nitrogen atom; F is a vinylene group or an oxygen atom, STR4 wherein R6 is a lower alkoxy group; R7 is a lower alkyl group; R8 is a benzoyl group which may be optionally substituted with at least one of the same or different halogen atom, B is a divalent azole group; R1 is a hydrogen atom or a lower alkyl group; R2 is a hydrogen atom, lower alkyl, aryl-lower alkyl, or the group of the formula: wherein R9 is a hydrogen atom, lower alkyl, halo-lower alkyl, amino-lower alkyl, aryl or aryl-lower alkyl group or the group of the formula: STR5 wherein R10 is a hydrogen atom or lower alkoxy group; R11 is a hydrogen atom, lower alkyl, lower alkenyl, lower cycloalkyl, aryl-lower alkyl, aryl or aroyl group; or the group of the formula: --NR10 R11 is a 5-, 6- or 7-membered saturated heterocyclic ring; or the group of the formula: wherein R12 is a lower alkyl or polyhalo-lower alkyl group; G is a divalent group selected from the group consisting of >C=O, >C=S, >(C=O)2 or >SO2 radical; or the group of the formula: --NR1 R2 is a 5-, 6- or 7-membered saturated heterocyclic ring: R3 is a hydrogen atom or lower alkyl group, or its acid addition salts, which is useful for immunomodulator.
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- A Simple and Efficient Conversion of Aldehyde Acetals into Esters
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The reaction of aldehydic acetals with hypochlorous acid in acetic acid-acetone afforded the corresponding esters in excellent yields.From cyclic acetals, only the corresponding hydroxyalkyl esters were obtained.Keywords - acetal; hypochlorite; hypochlorous acid; conversion; ester; hydroxyalkyl ester; regioselectivity
- Sugai, Saburo,Kodama, Takashi,Akaboshi, Sanya,Ikegami, Shiro
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- Therapeutically active phenylalkane derivatives
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2-(2-Fluoro-4-biphenylyl)propan-1-ol, 2-(2'-Fluoro-4-biphenylyl)propan-1-ol and 2-(2,2'-Difluoro-4-biphenylyl)propan-1-ol Possessing great anti-inflammatory, analgesic and antipyretic activities.
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