- Design, synthesis, and antitumor activity of novel quinazoline derivatives
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In an attempt to explore a new class of epidermal growth factor receptor (EGFR) inhibitors, novel 4-stilbenylamino quinazoline derivatives were synthesized through a Dimorth rearrangement reaction and characterized via IR, 1H-NMR, 13C-NMR, and HRMS. Methoxyl, methyl, halogen, and trifluoromethyl groups on stilbeneamino were detected. These synthesized compounds were evaluated for antitumor activity in vitro against eight human tumor cell lines with an MTS assay. Most synthesized compounds exhibited more potent activity (IC50 = ~2.0 μM) than gefitinib (IC50 > 10.0 μM) against the A431, A549, and BGC-823 cell lines. Docking methodology of compound 6c and 6i binding into the ATP site of EGFR was carried out. The results showed that fluorine and trifluoromethyl played an important role in efficient cell activity.
- Wang, Liuchang,Li, Pengna,Li, Baolin,Wang, Yawen,Li, Jiangtao,Song, Limei
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Read Online
- Synthesis and biological evaluation of selenogefitinib for reducing bleomycin-induced pulmonary fibrosis
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Selenium has demonstrated effectiveness in the reduction of oxidative stress and inflammation in vitro and in vivo, both of which are key indicators of the pathogenesis of pulmonary fibrosis. Gefitinib, an FDA-approved EGFR inhibitor, effectively reverses
- Bai, Yue,Chen, Lixue,Chu, Peng,Han, Xu,Li, Lei,Li, Yanxia,Ma, Xiaodong,Qi, Yan,Sun, Huijun,Wang, Changyuan,Zhang, Baojing,Zhang, Yunhao
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supporting information
(2021/07/08)
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- Iron-catalyzed arene C-H hydroxylation
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The sustainable, undirected, and selective catalytic hydroxylation of arenes remains an ongoing research challenge because of the relative inertness of aryl carbon-hydrogen bonds, the higher reactivity of the phenolic products leading to over-oxidized by-products, and the frequently insufficient regioselectivity. We report that iron coordinated by a bioinspired L-cystine-derived ligand can catalyze undirected arene carbon-hydrogen hydroxylation with hydrogen peroxide as the terminal oxidant. The reaction is distinguished by its broad substrate scope, excellent selectivity, and good yields, and it showcases compatibility with oxidation-sensitive functional groups, such as alcohols, polyphenols, aldehydes, and even a boronic acid. This method is well suited for the synthesis of polyphenols through multiple carbon-hydrogen hydroxylations, as well as the late-stage functionalization of natural products and drug molecules.
- Cheng, Lu,Wang, Huihui,Cai, Hengrui,Zhang, Jie,Gong, Xu,Han, Wei
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- Method for promoting iron-catalyzed oxidation of aromatic compound carbon - hydrogen bond to synthesize phenol by ligand
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The method comprises the following steps: iron is used as - a catalyst metal; a sulfur-containing amino acid or cystine-derived dipeptide is a ligand; and under the common action of hydrogen peroxide as an oxidizing agent, an aromatic compound is synthesized to prepare a phenol. Under the action of an acid as an accelerant and hydrogen peroxide as an oxidizing agent, the aryl carbon - hydrogen bond is directly hydroxylated to form a phenolic compound, and the method for preparing the phenol by the catalytic oxidation reaction has a plurality of advantages. The reaction raw materials, the oxidant and the promoter are wide in source, low in price, environment-friendly and good in stability. The aromatic compound carbon - hydrogen bonds directly participate in the reaction to react in one step to form phenol. The reaction condition is mild, the functional group compatibility and the application range are wide. The reaction selectivity is good; under the optimized reaction conditions, the target product separation yield can reach 85%.
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Paragraph 0066-0667; 0127
(2021/09/21)
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- Preparation method of high-purity gefitinib key intermediate
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The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a high-purity gefitinib key intermediate 6-hydroxy-7-methoxy-3H-quinazoline-4-ketone. The synthesis method is simple to operate, the yield is high, t
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Paragraph 0018; 0019
(2020/05/02)
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- Quinazolinone compounds as well as preparation method and application thereof
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The invention relates to quinazolinone compounds as well as a preparation method and application thereof, three kinases of EGFR (epidermal growth factor receptor), VEGFR-2 (vascular endothelial growthfactor receptor 2) and FGFR1 (fibroblast growth factor
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Paragraph 0035-0036
(2020/04/02)
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- 4-anilinoquinazoline derivative and albumin conjugates thereof
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a pharmaceutical composition for preventing, treating, or ameliorating one or more symptoms of a malignant tumor associated with EGFR mutation and/or K-RAS mutation is provided. The pharmaceutical composition includes a 4-anilinoquinazoline derivative having a formula (I) where A is iodine when m is 1 and n is zero, or A is albumin when m is an integral ranging from 1 to 7 and n is 1.
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Page/Page column 5
(2019/04/26)
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- A high-purity of gefitinib preparation method
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The invention relates to a process for preparing high-purity of gefitinib method the method comprises the following 5 steps: 1st step exotic fragrance orchid [...], 2nd step etherification, 3rd step nitration, step reduction 4th, 5th step ring gathers passes through purification of the final product is obtained. The programme raw material sources are extensive, the cost is reduced, improving the quality of products, it is easy to further popularization and application.
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Paragraph 0014
(2019/04/04)
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- Preparing method of gefitinib intermediate
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The invention discloses a preparing method of a gefitinib intermediate. The method includes the following steps of firstly, making a compound 1 react in the presence of sodium formate, formic acid andhydroxylamine sulphate to obtain a compound 2; secondly, making the compound 2 and a compound 3 react in the presence of potassium carbonate in a first solvent to obtain a compound 4; thirdly, makingthe compound 4 react in the presence of sulfuric acid and nitric acid in a second solvent to obtain a compound 5; fourthly, making the compound 5 react in the presence of alkaline and hydrogen peroxide in a third solvent to obtain a compound 6; fifthly, making the compound 6 react in the presence of ammonium formate and palladium/carbon in a fourth solvent to obtain a compound 7; sixthly, makingthe compound 7 react in the presence of formic acid and formamide to obtain a compound 8.
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Paragraph 0021; 0022; 0023
(2019/05/04)
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- New synthesis method of gefitinib
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The invention relates to a new synthetic method of an anti-tumor drug 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinylpropoxy)quinazoline (gefitinib, I). According to the synthesis method,synthesis is performed through a novel synthetic intermediate. Before a quinazoline mother ring is synthesized, hydroxy of 3-hydroxy-4-methoxybenzonitrile is reacted with 3-morpholinopropyl chloride firstly, so that the steps of adding protecting groups and removing the protecting groups are reduced, the synthesis route is shortened, the step number of synthesis is lowered, raw materials are cheapand easily obtained, the use of chlorinated reagents which heavily pollute the environment is avoided, the purification process is simplified, the pH (potential of hydrogen) value does not need to berepeatedly adjusted, the operation is safe and simple, and the reaction yield exceeds 60%.
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Paragraph 0008; 0015
(2018/04/02)
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- Synthesis and biological assay of erlotinib analogues and BSA-conjugated erlotinib analogue
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A series of erlotinib analogues that have structural modification at 6,7-alkoxyl positions is efficiently synthesized. The in vitro anti-tumor activity of synthesized compounds is studied in two non-small cell lung cancer (NSCLC) cell lines (A549 and H1975). Among the synthesized compounds, the iodo compound 6 (ETN-6) exhibits higher anti-cancer activity compared to erlotinib. An efficient method is developed for the conjugation of erlotinib analogue-4, alcohol compound, with protein, bovine serum albumin (BSA), via succinic acid linker. The in vitro anti-tumor activity of the protein attached erlotinib analogue, 8 (ETN-4-Suc-BSA), showed stronger inhibitory activity in both A549 and H1975 NSCLC cell lines.
- Boobalan, Ramalingam,Liu, Kuang-Kai,Chao, Jui-I.,Chen, Chinpiao
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supporting information
p. 1784 - 1788
(2017/04/04)
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- Preparation method of Apremilast
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The invention relates to a preparation method of Apremilast, comprising the following steps: by taking 3-hydroxy-4-methoxybenzaldehyde as a staring material, reacting with hydroxylamine hydrochloride to obtain 3-hydroxy-4-methoxy cyanobenzene, reacting with bromoethane to obtain 3-ethyoxyl-4-methoxy cyanobenzene, and then reacting with dimethyl sulfone under the action of n-butyllithium, and hydrolyzing in aqueous hydrochloric acid solution to obtain 1-(3-ethyoxyl-4-methoxyphenyl)-2-(mesyl)ketol); finally by taking S-(-)-alpha, alpha-diphenyl-2-pyrrolidine methanol as a chiral catalyst and taking borane dimethyl sulfide complex solution as a reductant, obtaining chirality S-3-ethyoxyl-4-methoxy group-alpha[(mesyl)benzyl alcohol], and then reacting with 3-acetamido-phthalimide under the action of triphenylphosphine and diethyl azodicarboxylate, thus obtaining the Apremilast. According to the preparation method, the process is effectively simplified, the reaction conditions are mild, the product yield and purity are relatively high, and large-scale industrial production is benefited.
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Paragraph 0055; 0056
(2016/11/28)
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- Preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol
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The invention relates to a preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol. The preparation method comprises the following steps: 3-hydroxy-4-methoxybenzaldehyde is taken as a starting material and reacts with hydroxylammonium hydrochloride to produce 3-hydroxy-4-methoxybenzonitrile; 3-hydroxy-4-methoxybenzonitrile reacts with bromoethane to produce 3-ethoxy-4-methoxybenzonitrile; 3-ethoxy-4-methoxybenzonitrile reacts with dimethyl sulfone under the action of n-butyllithium, a product is hydrolyzed in an aqueous hydrochloric acid solution, and 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone is obtained; finally, S-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol or R-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol is taken as a chiral catalyst, a borane dimethyl sulfide solution is taken as a reducing agent, carbonyl is reduced, and a product is obtained. The reaction conditions are mild, the product yield is higher, the technology level is increased, the operability is improved, and large-scale industrial production is facilitated.
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Paragraph 0049; 0050
(2016/12/12)
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- Optimization of gefitinib analogues with potent anticancer activity
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The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues.
- Yin, Kai-Hao,Hsieh, Yi-Han,Sulake, Rohidas S.,Wang, Su-Pei,Chao, Jui-I.,Chen, Chinpiao
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supporting information
p. 5247 - 5250
(2015/01/08)
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- NBS mediated nitriles synthesis through CC double bond cleavage
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An NBS mediated nitriles synthesis through CC double bond cleavage has been developed. TMSN3 was employed as the nitrogen source for this Cu(OAc)2 promoted nitrogenation reaction. This transformation has a relatively high regio-selectivity to form aromatic nitriles.
- Zong, Xiaolin,Zheng, Qing-Zhong,Jiao, Ning
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supporting information
p. 1198 - 1202
(2014/03/21)
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- SUBSTITUTED NAPHTHYRIDINES AND THEIR USE AS MEDICAMENTS
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The invention relates to new substituted naphthyridines of formula 1, as well as pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof, wherein R1 is selected from among —O—R3 or —NR3R4,R3 is C1-6-alkyl which is substituted by R5 and R6,R5 is selected from hydrogen, branched or linear C1-6-alkyl, C2-6-alkenyl, —C1-6-alkylen-O—C1-3-alkyl, C1-3-haloalkyl,R6 is ring X wherein n is either 0 or 1, and is a either a single or a double bond andwherein A, B, D and E are each independently from one another selected from CH2, CH, C, N, NH, O or S and wherein ring X is attached to the molecule either via position A, B, D or E, wherein said ring X may optionally be further substituted by one, two or three residues each selected individually from the group consisting of -oxo, hydroxy, —C1-3-alkyl, —C1-3-haloalkyl, —O—C1-3-alkyl, —C1-3-alkanol and halogen,and wherein R4, R2, R7, R8, R9, R10, R11 and Q may have the meanings as given in claim 1, as well as pharmaceutical compositions containing these compounds.
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Page/Page column 18
(2012/02/06)
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- Design and Synthesis of 3,5-Disubstituted-1,2,4-Oxadiazoles as Potent Inhibitors of Phosphodiesterase4B2
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A series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC50=5.28μm). Structure-activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat.
- Kumar, Dalip,Patel, Gautam,Vijayakrishnan, Lalitha,Dastidar, Sunanda G.,Ray, Abhijit
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scheme or table
p. 810 - 818
(2012/06/18)
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- SUBSTITUTED NAPHTHYRIDINES AND THEIR USE AS SYK KINASE INHIBITORS
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The invention relates to new substituted naphthyridines of formula (1), as well as pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof, wherein R1 is selected from among -O-R3 or -NR3R4, R3 is C1-6-alkyl which is substituted by R5 and R6 R5 is selected from hydrogen, branched or linear C1-6-alkyl, C2-6-alkenyl, -C1-6-alkylen-O-C1-3-alkyl, C1-3-haloalkyl, R6 is ring X wherein n is either 0 or 1, and Formula (I) is a either a single or a double bond and wherein A, B, D and E are each independently from one another selected from CH2, CH, C, N, NH, O or S and wherein ring X is attached to the molecule either via position A, B, D or E, wherein said ring X may optionally be further substituted by one, two or three residues each selected individually from the group consisting of -oxo, hydroxy, -C1-3-alkyl, -C1-3-haloalkyl, -O-C1-3-alkyl, -C1-3-alkanol and halogen, and wherein R4, R2, R7, R8, R9, R10, R11 and Q may have the meanings as given in claim 1, as well as pharmaceutical compositions containing these compounds.
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Page/Page column 37
(2011/08/21)
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- Environment friendly protocol for the synthesis of nitriles from aldehydes
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A rapid and eco-friendly one-pot protocol for the synthesis of nitriles has been developed by treating various araldehydes bearing electron withdrawing as well as electron donating groups with hydroxylamine hydrochloride in the presence of non-toxic, non-corrosive and reusable zinc oxide (ZnO) as the catalyst under solvent-free microwave irradiation. The present approach offers the advantages of a clean reaction, simple methodology, employing readily available catalyst, short reaction duration (1. min), high selectivity; and high yield (90-98%).
- Madhusudana Reddy,Pasha
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experimental part
p. 1025 - 1028
(2011/10/08)
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- Synthesis of [11C]Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase
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Iressa (Gefitinib) is an orally active inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) involved in cell signal transduction processes critical to proliferation, apoptosis, repair, and angiogenesis of cancer cells. [11C]Iressa was first designed and synthesized as a new potential positron emission tomography (PET) cancer imaging agent for EGFR-TK in 30-40% radiochemical yield with 4.0-6.0 Ci/μmol specific activity at end of bombardment (EOB).
- Wang, Ji-Quan,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
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p. 4102 - 4106
(2007/10/03)
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- PROCESS FOR THE MANUFACTURE OF GEFITINIB
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The invention relates to a process for the manufacture of 4-(3'-chloro-4'- fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline which comprises the rearrangement reaction optionally in the presence of a suitable catalyst of 3-(3'-chloro-4'-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin- 4-imine of Formula (II).
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Page/Page column 16
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF 4-(3'-CHLORO-4'-FLUOROANILINO)-7-METHOXY-6-(3-MORPHOLINOPROPOXY) QUINAZOLINE
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The invention relates to chemical processes and intermediates useful in the manufacture of the quinazoline derivative 4 (3'' chloro 4'' fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline. In particular, the invention relates to processes for the manufacture of 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one of Formula (II) and 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile of Formula (III) and their use in the manufacture of said quinazoline derivative
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- Imidazopyrimidine derivatives and triazolopyrimidine derivatives
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A compound of the formula (I) wherein R1 is —X—R4, an optionally substituted heterocyclic residue, an optionally substituted carbocyclic residue or optionally substituted condensed ring moiety; X is CR5R6, O, S, SO, SO2 or NR7; Y is CH or N; R2 is H, an optionally substituted C1-C10 alkyl,etc.; R3 is an optionally substituted aryl, or an optionally substituted heteroaryl, etc.; R4 is an optionally substituted aryl, an optionally substituted heteroaryl, etc.; R5, R6, and R7 can be identical or different and represent H, an optionally substituted C1-C10 alkyl, etc. The compound has an excellent anti-allergic activity and the like.
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- Practical synthesis of a highly functionalized thiazole ketone
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Compound 1 is a uniquely substituted ketone prepared via addition of a thiazole anion to an aromatic nitrile in good overall yield. An exploration into the generality of the addition of thiazole anions to nitriles allowed us to make a variety of thiazole ketones in good to excellent yields. The non-odorous thiolate-mediated demethylation reaction used in the synthesis of 1 is also presented.
- Frey, Lisa F.,Marcantonio, Karen M.,Chen, Cheng-Yi,Wallace, Debra J.,Murry, Jerry A.,Tan, Lushi,Chen, Weirong,Dolling, Ulf H.,Grabowski, Edward J. J.
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p. 6363 - 6373
(2007/10/03)
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- Sodium bis(trimethylsilyl)amide in the 'one-flask' transformation of aromatic esters to nitriles
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A new 'one-flask' method was developed for the conversion of aromatic esters to the corresponding nitriles by use of sodium bis(trimethylsilyl)amide.
- Hwu, Jih Ru,Hsu, Chia Hao,Wong, Fong Fuh,Chung, Chung-Sun,Hakimelahi, Gholam H.
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p. 329 - 332
(2007/10/03)
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- SUBSTITUENT EFFECTS IN AROMATIC PHOTOCHEMISTRY: UV IRRADIATION OF 3,4-DIMETHOXYBENZONITRILE AND 3,4-DIMETHOXYACETOPHENONE IN THE PRESENCE OF INORGANIC ANIONS
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Ultraviolet photolysis of 3,4-dimethoxybenzonitrile (Ia) and 3,4-dimethoxyacetophenone (IIa) in the presence of the hydroxide or cyanide anions leads to nucleophilic displacement of either the para or the meta methoxy substituent.The ratio of isomeric photoproducts is dependent upon the nature of the nucleophile.Photoreactions with the OH(-) anion leads exclusively to the substitution at C-3.On the other hand, both isomers are formed when acetophenone IIa is irradiated in the presence of CN(-), with the C-3/C-4 ratio ranging from 1:2 to 1:6 in dependence on the nucleophile concentration.These difference between the OH(-) and CN(-) anion are related to the results of a fluorescence quenching study which has revealed that only the observed for the quenching of the second excited state of Ia by the cyanide anion.This indicates several distinct quenching modes, in relation to the concentration dependence of regioselectivity.The activating power of -H, -CN, -COCH3, and -NO2 substituents, as measured by relative quantum yields of disappearance for 3,4-dimethoxy-R-substituted benzenes, is 1 : 2.5 : 5 : 580 and 1 : 1.5 : 6 : 1000 in their photoreactions with OH(-) and CN(-) anions, respectively.
- Kuzmic, Petr,Soucek, Milan
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p. 980 - 988
(2007/10/02)
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