- Hydrolysis of Barbituric Acid Derivatives. Part 6. Hydrolysis of Spirocyclopropane- and Spiro-2'-methylcyclopropane-1',5-barbituric Acids
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The title barbiturates are hydrolysed by pyrimidine ring degradation or by cyclopropane ring opening.The cyclopropane ring decreases the hydrolytic reactivity of the pyrimidine moiety in relation to other spirobarbiturates, owing to conjugation between the cyclopropane ring and the C-4 or C-6 carbonyl group.The kinetics and the products of the alcoholysis of these barbiturates have been investigated.The influence of the cyclopropane moiety on the pKa1 values and 13C n.m.r. spectra has also been discussed.
- Mokrosz, Jerzy L.,Paluchowska, Maria H.
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- Synthesis of Spirooxindoles from N-Arylamide Derivatives via Oxidative C(sp2)-C(sp3) Bond Formation Mediated by PhI(OMe)2 Generated in Situ
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A class of novel spirooxindole compounds (2) were readily synthesized, in a metal-free environment, from N-arylamide derivatives (1) via intramolecular oxidative cyclization. Direct oxidative C(sp2)-C(sp3) bond formation was realized with the least-studied PhI(OMe)2 as an oxidant, formed in situ from the reaction between PhIO and MeOH.
- Zhen, Xiaohua,Wan, Xintong,Zhang, Wei,Li, Qiao,Zhang-Negrerie, Daisy,Du, Yunfei
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- 1, 1-cyclopropane dicarboxylic acid amide compound as well as preparation method and application thereof
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The invention discloses a 1, 1-cyclopropane dicarboxylic acid amide compound as well as a preparation method and application thereof, and the structural formula of the 1, 1-cyclopropane dicarboxylic acid amide compound is as shown in a formula (I): in the formula (I), the structures of two substituted benzene rings are the same, the number of substituents R on each substituted benzene ring is 1-3,and the substituent R is selected from H, halogen, C1-C4 alkyl, C2-C4 ester group or C1-C3 alkoxy. The 1, 1-cyclopropane dicarboxylic acid amide compound provided by the invention is a novel compoundwith an efficient weeding effect, and provides a basis for research and development of novel herbicides.
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Paragraph 0024; 0028; 0031
(2021/01/11)
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- Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2
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c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
- Shi, Wei,Qiang, Hao,Huang, Dandan,Bi, Xinzhou,Huang, Wenlong,Qian, Hai
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p. 814 - 831
(2018/09/29)
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- Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors
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Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
- Li, Jieming,Gu, Weijie,Bi, Xinzhou,Li, Huilan,Liao, Chen,Liu, Chunxia,Huang, Wenlong,Qian, Hai
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supporting information
p. 6674 - 6679
(2017/11/28)
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- Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2
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The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210?nM and 170?nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
- Qiang, Hao,Gu, Weijie,Huang, DanDan,Shi, Wei,Qiu, Qianqian,Dai, Yuxuan,Huang, Wenlong,Qian, Hai
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supporting information
p. 3353 - 3358
(2016/07/20)
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- Arene oxidation with malonoyl peroxides
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Malonoyl peroxide 7, prepared in a single step from the commercially available diacid, is an effective reagent for the oxidation of aromatics. Reaction of an arene with peroxide 7 at room temperature leads to the corresponding protected phenol which can be unmasked by aminolysis. An ionic mechanism consistent with the experimental findings and supported by isotopic labeling, Hammett analysis, EPR investigations, and reactivity profile studies is proposed.
- Dragan, Andrei,Kubczyk, Tomasz M.,Rowley, Julian H.,Sproules, Stephen,Tomkinson, Nicholas C. O.
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supporting information
p. 2618 - 2621
(2015/06/16)
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- A convenient synthesis of cyclopropane malonyl peroxide
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Cyclopropane-1,1-dicarbonyl peroxide was prepared in 85% yield by the reaction of diethyl cyclopropane-1,1-dicarboxylate with the urea hydrogen peroxide clathrate in the presence of methanesulfonic acid.
- Terent'Ev, Alexander O.,Vil', Vera A.,Mulina, Olga M.,Pivnitsky, Kazimir K.,Nikishin, Gennady I.
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p. 345 - 345
(2015/02/19)
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- Synthesis, crystal structure and bioactivity of N-(5-propyl-1,3,4- thiadiazol-2-yl)cyclopropanecarboxamide
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A new 1,3,4-thiadiazole compound with m.f. C9H 13N3OS, has been synthesized and confirmed by 1H NMR and HRMS. The single crystal structure of the 1,3,4-thiadiazole compound was determined by a single crystal X-ray diffraction study. The crystal belongs to the triclinic system, space group P-1 with a = 10.238(2), b = 10.325(2), c = 10.560(2) ?, α = 104.09(3), β = 109.50(3), γ = 93.40(3)°, Z = 4, V = 1008.4(3)?3, Mr = 211.28, Dc = 1.392 g/cm3, S = 0.98, μ = 0.29 mm-1, F(000) = 448, the final R1 = 0.0970 and wR2 = 0.2147 for 1776 were observed with I > 2Σ(I). X-ray indicated that two intermolecular hydrogen bonds N1-H1···N5, N4-H4···N2 were observed. The preliminary biological test shown that the synthesized compound has moderate herbicidal activity against Brassica campestris.
- Sun, Na-Bo,Jin, Jian-Zhong,Lei, Chao,He, Fang-Yue
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p. 7820 - 7822
(2013/09/23)
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- Synthesis, crystal structure and biological activity of N-(5-(o-tolyl)-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamide
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A new 1, 3, 4-thiadiazole compound, N-(5-(o-tolyl)-1,3,4-thiadiazol-2-yl) cyclopropanecarboxamide, was synthesized and its structure was confirmed by 1H NMR, MS and HRMS. The single crystal structure of the title compound was determined by X-ray diffraction. The preliminary biological test showed that the synthesized compound has moderate herbicidal activity against Brassica campestris and fungicidal activities against Sclerotinia sclerotiorum(Lib.) de Bary, Rhizoctonia solanii, Fusarium oxysporum, Corynespora cassiicola, and Botrytis cinerea.
- Tong, Jian-Ying,Sun, Na-Bo,Wu, Hong-Ke,Liu, Xing-Hai
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p. 1349 - 1353
(2014/01/06)
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- Alkene dihydroxylation with malonoyl peroxides: Catalysis using fluorinated alcohols
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The effect of fluorinated alcohols on the dihydroxylation of alkenes using cyclopropyl malonoyl peroxide is described. Addition of perfluoro-tert-butyl alcohol to a toluene solution of alkene and peroxide increases the rate of product formation and the stereoselectivity observed, providing a simple and effective method for acceleration of this important class of reaction. Basic hydrolysis of the crude reaction mixture provides access to syn-diols in high yield and stereoselectivity.
- Picon, Sylvain,Rawling, Michael,Campbell, Matthew,Tomkinson, Nicholas C. O.
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p. 6250 - 6253
(2013/02/23)
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- Synthesis, antifungal activities and 3D-QSAR study of N-(5-substituted-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamides
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A series of cyclopropanecarboxamide were prepared and tested for antifungal activity in vivo. The preliminary bioassays indicated that some compounds are comparable to the commercial fungicides. To further explore the comprehensive structure-activity relationship on the basis of fungicidal activity data, comparative molecular field analysis (CoMFA) was performed, and a statistically reliable model with good predictive power (r2 = 0.8, q2 = 0.516) was achieved. Based on the CoMFA, compound 7p was designed and synthesized, which was found to display a good antifungal activity (79.38%) as 7g and 7h.
- Liu, Xing-Hai,Shi, Yan-Xia,Ma, Yi,Zhang, Chuan-Yu,Dong, Wei-Li,Pan, Li,Wang, Bao-Lei,Li, Bao-Ju,Li, Zheng-Ming
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scheme or table
p. 2782 - 2786
(2009/10/19)
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- Practical synthesis of a heterocyclic immunosuppressive vitamin D analogue
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1α,25-Dlhydroxyvitamin D3 (calcitrioi) 1 and synthetic analogues thereof are highly potent compounds with a wide range of pharmacological activity making them of great interest for the pharmaceutical industry. Herein we report an improved synthesis of the calcitriol analogue 2, which features a novel oxazole-containing side chain. The crucial part of the synthesis was the development of a practical route to the β-keto phosphonate 28, allowing an easy introduction of the unnatural side chain by a Wittig Horner reaction.
- Westermann, Juergen,Schneider, Matthias,Platzek, Johannes,Petrov, Orlin
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p. 200 - 205
(2012/12/26)
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- NUCLEOSIDE PHOSPHONATE DERIVATIVES USEFUL IN THE TREATMENT OF HIV INFECTIONS
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The present invention relates to a method of treating HIV infections by administering a nucleoside phosphonate derivative represented by formula (I).
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Page/Page column 51
(2008/06/13)
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- Selective reactions of 1,1-cycloalkanedicarboxylic acids with SF4. a route to 1,1-bis(trifluoromethyl)cycloalkanes, 1-fluoroformyl-1-(trifluoromethyl)cycloalkanes and 1-(trifluoromethyl)-1-cycloalkanecarboxylic acids
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Six-, five-, four- and three-membered 1,1-cycloalkanedicarboxylic acid (2a-d) were synthesized by alkaline hydrolysis of the corresponding diesters (1a-d) and the reactions of the formers with SF4 were investigated. 1,1-Bis(trifluoromethyl)cycloalkanes (3a-d) were the products of the reactions conducted at 120-150°C while at 30°C 1-fluoroformyl-1-(trifluoromethyl)cycloalkanes (4a-d) were exclusively formed. The latter were isolated as pure compounds or converted in situ into 1-(trifluoromethyl)-1-cycloalkanecarboxylic acids (5a-d).
- Dmowski, Wojciech,Wolniewicz, Adam
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p. 141 - 146
(2007/10/03)
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- Process for preparing malonic acid and alkylmalonic acids
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Malonic acid and alkylmalonic acids are prepared by a process of acid-catalyzed saponification of malonic acid esters, which comprises: contacting an aqueous mixture of the ester II with an acid ion exchanger containing sulfonic acid groups at from 30°-100° C. and from 40-1000 mbar according to the following scheme: STR1 where R1 =H, CH3, R2 =H, CH3 or R1 +R2 =--CH2 --CH2 --and R3 =CH3, C2 H5, C3 H7, C(CH3)3 ; distilling off the alcohol R3 OH which is formed; separating the water, with the aid of organic solvents, from the malonic acid or alkylmalonic acid product; and then isolating the product by crystallization.
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- Process for preparing alkyl- and arylmalonic acids
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Alkyl- and arylmalonic acids of the formula I STR1 where R1 =H, C1 -C12 -alkyl, phenyl, C1 -C4 -alkylphenyl, C2 -C4 -dialkylphenyl, R2 =C1 -C12 -alkyl, phenyl, C1 -C4 -alkylphenyl, C2 -C4 -dialkylphenyl or R1 +R2 =--CH2 --CH2 --, are prepared by alkaline saponification by hydrolyzing the corresponding C1 -C4 -alkyl esters of the malonic acid of formula I, with alkali metal hydroxide dissolved in an aqueous alkali metal salt solution containing salt at 90-100% of saturation, acidifying the hydrolysis product with a mineral acid, removing the precipitated alkali metal salt which forms upon acidification, and extracting the alkyl- and arylmalonic acid formed from the aqueous solution with the aid of an organic solvent.
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- Preparation and Cleavage of Some Cyclopropane Derivatives
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Alkylation of active methylene compounds with 1,2-dibromoethane using anhyd.K2CO3/DMF at room temperature gives cyclopropane derivatives which undergo selective transformation by simple methods.Cyclopropanes, obtained by the condensation of α-diazoacetophenones with olefins, are cleaved to trisubstituted olefins with Grignard reagent.Hydration of the products has also been studied.
- Podder, Ranjan Kumar,Sarkar, Ranjit Kumar,Ray, Suvas C.
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p. 530 - 536
(2007/10/02)
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- Dimerization of Cyclopropanecarboxylic Acid Dianion and Thermal Decarboxylative Rearrangement of the Dimer to 2-Cyclopropyl-4,5-dihydrofuran
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The dianion of cyclopropanecarboxylic acid (2) reacted with alkyl halides and deuterated water at temperatures below 0 deg C; however, self-condensation to the β-keto acid 3 was the only observed product at elevated temperatures.This observation contrasts the self-condensation of the ethyl ester where a trimeric diester alcohol is the product.Attempted mixed condensations of the dianion 2 and carboxylic acids without acidic α-protons did not proceed as well, 3 being the major product.Thermal decarboxylation of 3 did not yield the expected dicyclopropyl ketone; rather , a facile rearrangement in a sealed tube at 120 deg C occured, giving rise to 2-cyclopropyl-4,5-dihydrofuran.This "vinyl-cyclopropyl" type rearrangement does not occur through dicyclopropyl ketone or its enolate.
- Jahngen, Edwin G. E.,Phillips, Douglas,Kobelski, Robert J.,Demko, Donald M.
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p. 2472 - 2476
(2007/10/02)
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