788136-89-0

Usage

Uses

Used in Pharmaceutical Industry:
4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate is used as an impurity in the production of Gefitinib (G304000), an antineoplastic drug. It is important to monitor and control the presence of this impurity to ensure the safety and efficacy of the final drug product.

InChI:InChI=1/C17H13ClFN3O3/c1-9(23)25-16-6-11-14(7-15(16)24-2)20-8-21-17(11)22-10-3-4-13(19)12(18)5-10/h3-8H,1-2H3,(H,20,21,22)

Upstream product

• 367-21-5 3-chloro-4-fluorophenylamine 
• 230955-75-6 6-acetoxy-4-chloro-7-methoxyquinazoline 
• 948551-62-0 C₁₁H₁₁ClN₂O₃ 
• 367-22-6 4-chloro-3-fluoroaniline 
• 20323-74-4 2-carboethoxy-4,5-dimethoxyaniline 
• 100905-33-7 ethyl 2-nitro-4,5-dimethoxybenzoate 
• 3943-77-9 ethyl veratrate 
• 93-07-2 Veratric acid 
• 26759-46-6 methyl 2-amino-4,5-dimethoxybenzoate 
• 4998-07-6 4,5-dimethoxy-2-nitro-benzoic acid 
• 20357-25-9 6-nitroveratraldehyde 
• 120-14-9 3,4-dimethoxy-benzaldehyde 
• 179688-53-0 (4-hydroxy-7-methoxyquinazolin-6-yl) acetate 
• 31839-21-1 2-amino-5-hydroxy-4-methoxybenzoic acid 

Downstream Products

• 1450754-57-0 6-(2-(3-(but-3-ynyl)-3H-diazirin-3-yl)ethoxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine 
• 1360859-35-3 6-(2-(2-aminoethylamino)ethoxy)-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy quinazoline 
• 1373944-38-7 4-(3-chloro-4-fluoroanilino)-6-(N-(2-aminoethyl)aminopropoxy)-7-methoxyquinazoline 
• 1428015-62-6 6-(2-aminoethoxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine 
• 1221965-74-7 M 527301 
• 184475-35-2 gefitinib 
• 295330-38-0 tert-butyl 4-[3-[4-(3-chloro-4-fluoro-anilino)-7-methoxy-quinazolin-6-yl]oxypropyl]piperazine-1-carboxylate 

Relevant academic research and scientific papers

Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors

Multi-target, especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized compounds were evaluated against epidermoid carcinoma (A431) and non-small cell lung cancer (A549 and H1975) cell lines, which displayed weak to potent anticancer activity. In particular, compound 8v emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib. Importantly, 8v exhibited stronger anti-proliferative activity than osimertinib against H1975 cells under hypoxic condition. Kinase inhibition studies indicated that 8v showed excellent inhibitory effect on EGFRT790M enzyme, which was 41 times more effective than gefitinib and almost equal to osimertinib. Mechanism studies revealed that 8v exhibited remarkable CAIX inhibitory effect comparable to acetazolamide and significantly inhibited the expression of p-EGFR as well as its downstream p-AKT and p-ERK in H1975 cells. Notably, 8v was found to inhibit the expression of CAIX and its upstream HIF-1α in H1975 cells under hypoxic condition. Molecular docking was also performed to gain insights into the ligand-binding interactions of 8v inside EGFRWT, EGFRT790M and CAIX binding sites.

A preparation method of gefitinib (by machine translation)

The present invention relates to organic chemical and medical technology field, in particular relates to a preparation method of gefitinib. The present invention provides a preparation method of gefitinib, obtained by formula I compounds, the formula I compound preparation method comprises the following steps: nitration reaction, oxidation reaction, selective demethylation reaction, reduction reaction, a cyclization reaction, phenolic hydroxyl acetylation reaction. The present invention provides a preparation method can at the same time reducing the cost, it is easy for the refined purification, easy preparation and control of related impurities, the overall preparation process routes are greatly optimized, is suitable for industrial scale production. (by machine translation)

Novel tinib-type compound, preparation method and application thereof

The invention provides a novel tinib-type compound shown as a structural formula (I), wherein R1 is selected from aryl or ceteroary the aryl or ceteroary is substituted by one or more of alkyl, halogen, aryl, alkynyl, cyano, trifluoromethyl, methoxy and halogenated benzyl; R2 is 1,4,7,10-tetraazacyclododecane or 1,4,7-triazacyclononane. The invention also provides application of the compound in preparation of antitumor medicines. The novel tinib-type compound has an obvious inhibiting effect for A549 cell lines, apoptosis of A549 cells can be obviously enhanced, and the effect is obviously superior to that of gefitinib. (The structural formula is shown in the specification).

EGFR PROTEOLYSIS TARGETING CHIMERIC MOLECULES AND ASSOCIATED METHODS OF USE

The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold

Adenosine triphosphate (ATP)-competitive inhibitors of the epidermal growth factor receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, some marketed drugs affect a transient beneficial response in EGFR mutant NSCLC patients. We reported a series of potential EGFR inhibitors through incorporation of macrocyclic polyamine into 4-anilinoquinazoline scaffold. It is expected that anilinoquinazoline part effectively bind to EGFR domain, while ATP molecules are captured by a macrocyclic polyamine moiety. In vitro experiments exhibited that most of tested compounds suppressed tumor cell proliferation more strongly than Gefitinib and Lapatinib (dual inhibitor of EGFR/HER2) as controls. In kinase assays, the compound 1f showed excellent dual inhibition activity toward EGFRWT (IC50 = 1.4 nM) and HER2 (IC50 = 2.1 nM). In vivo pharmacology evaluation of 1f showed significant antitumor activity (TGI = 44.2%) in A549 xenografts mice. The current work provided a feasible solution to optimize anilinoquinazoline-based inhibitors.

Facile Synthesis of Novel Perfluorocarbon-Modulated 4-Anilinoquinazoline Analogues

4-Anilinoquinazoline analogues stand out among many kinds of small molecules that inhibit the tyrosine kinase activities of epidermal growth factor receptor (EGFR), thus serving as significant molecular targets for anticancer drug design. Herein, a series of novel perfluorocarbon (PFC) modulated 4-anilinoquinazolines were designed and prepared straightforwardly by nucleophilic substitution reaction of various anilinoquinazolines and PFC-derived methanesulfonate. In the presence of base, the reaction proceeded smoothly to afford a wide range of 4-anilinoquinazolines with different substituents on aniline moiety in good to high yields. Furthermore, the PFC-modified analogues of gefitinib and erlotinib were also obtained in 93% and 90% respectively, which may have potential for developing new inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase and fluorinated contrast agents (CA) for 19F MRI.

Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs

A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In?vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50of 7.4?nM and 82?nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468?cells. In?vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100?mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900?mg/kg (single dose).

Preparation method of gefitinib intermediate

The invention discloses a preparation method of a gefitinib intermediate. The preparation method comprises steps as follows: 1) in the presence of anion exchange resin, 6-acetoxyl-7-methoxy-3,4-dihydroquinazoline-4-ketone and sulfonyl chloride are subjected to a contact reaction in acetonitrile, after the reaction ends, ice water quenching, dichloromethane extraction and concentration under the reduced pressure are performed, and 6-acetoxyl-4-chloro-7-methoxyquinazoline is obtained, wherein the temperature for the contact reaction ranges from 65 DEG C to 75 DEG C; 2) in the presence of AuCl, 6-acetoxyl-4-chloro-7-methoxyquinazoline obtained in the step 1) and 3-chloro-4-fluoroaniline are subjected to a substitution reaction at the temperature of 55-65 DEG C, and the gefitinib intermediate is obtained. By means of the method, the product yield can be greatly increased, the conditions are mild, and few by-products are produced.

Quinazoline derivative and preparation method thereof

The invention relates to a quinazoline derivative and a preparation method thereof. 4-(3-amino)phenyl-6-aminoethoxy-7-methoxyquinazoline and 1,2,3-triazole-4-aldehyde are added to a reactor, a reaction solvent and a catalyst are added, and the mixture is evenly stirred and is subjected to a reaction at 80-120 DEG C; after the reaction is completed, a product is cooled to the room temperature, the solvent is removed through reduced pressure distillation, an obtained solid is recrystallized with ethanol, and an off-white solid is obtained through vacuum drying. According to the quinazoline derivative, quinazoline, Schiff base and a triazole group are organically combined, so that the derivative has a certain anti-tumor effect and is also beneficial to reducing the possibility of drug resistance of tumor cells. The synthetic route has the advantages that raw materials are easy to obtain, operation is simple, the solvent is saved, pollution is reduced and the like, and industrial production is facilitated.

Artemisin derivative and its preparation and use

Provided are artemisinin derivatives of formula (I) or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, and racemic bodies thereof, and a pharmaceutical composition of the compounds, the preparation process and uses thereof. Artemisinin derivatives of formula (I) have excellent effects in the treatment of tumours.