848133-76-6

Basic information

• Product Name: n-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl) acetamide
• Synonyms: N-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl);n-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl) acetamide;N-(4-CHLORO-3-CYANO-7-ETHOXY-6-QUINOLINYL) ACETAMI;Acetamide, N-(4-chloro-3-cyano-7-ethoxy-6-quinolinyl)-;4-chloro-3-cyano-7-ethoxy-6-N-acetylquinoline;N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetaMide;Neratinib Intermediate 2;n-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl) acetamide(848133-76-6)
• CAS NO: 848133-76-6
• Molecular Formula: C₁₄H₁₂ClN₃O₂
• Molecular Weight: 289.71698
• EINECS: 1592732-453-0
• Mol File: 848133-76-6.mol

Chemical Properties

• Melting Point: 250°C(lit.)
• Boiling Point: 518.6 °C at 760 mmHg
• Flash Point: 267.5 °C
• Appearance: /
• Density: 1.35 g/cm³
• Vapor Pressure: 7.35E-11mmHg at 25°C
• Refractive Index: 1.624
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly, Heated)
• PKA: 13.13±0.43(Predicted)
• CAS DataBase Reference: n-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl) acetamide(CAS DataBase Reference)
• NIST Chemistry Reference: n-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl) acetamide(848133-76-6)
• EPA Substance Registry System: n-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl) acetamide(848133-76-6)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Hazardous Substances Data: 848133-76-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
n-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl) acetamide is used as a key intermediate in the synthesis of neratinib (N390090), an antitumor agent. It plays a crucial role in the development of cancer treatments, specifically for targeted therapies against certain types of tumors.

InChI:InChI=1/C14H12ClN3O2/c1-3-20-13-5-11-10(4-12(13)18-8(2)19)14(15)9(6-16)7-17-11/h4-5,7H,3H2,1-2H3,(H,18,19)

Upstream product

• 126360-59-6 methyl 3-(N-acetyl)amino-4-hydroxybenzoate 
• 536-25-4 methyl 3-amino-4-hydroxybenzoate 
• 108-24-7 acetic anhydride 
• 1356916-92-1 3-acetamido-4-ethoxybenzoic acid 
• 91004-38-5 3-acetamido-4-hydroxybenzoic acid 
• 1571-72-8 3-amino-4-hydroxybenzoic acid 
• 74896-30-3 1-<3-(acetylamino)-4-hydroxyphenyl>ethanone 
• 54255-50-4 3-amino-4-hydroxyacetophenone 
• 1201079-10-8 1-(5-acetamido-4-ethoxy-2-nitrophenyl)ethanone 
• 1201079-07-3 1-(3-acetamido-4-ethoxyphenyl)ethanone 
• 16323-09-4 N-(4-chloro-2-hydroxyphenyl)acetamide 
• 860742-51-4 N-(4-chloro-2-ethoxyphenyl)acetamide 
• 28443-50-7 2-amino-5-chlorophenol 
• 1201080-09-2 N-(3-cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide 

Downstream Products

• 1025997-45-8 N-[4-(1-benzyl-2,3-dihydro-1H-indol-5-ylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-acetamide 
• 915941-95-6 N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide 
• 848655-77-6 N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide 
• 1246087-09-1 3-cyano-6-amino-7-ethoxy-4-(3-ethynylanilino)quinoline 
• 1259519-20-4 (E)-N-{[4-(3-ethynylphenylamino)-3-cyano-7-ethoxy-6-quinolyl]}-4-(dimethylamino)-2-butenoic acid amide 

Relevant articles and documents

Design, synthesis and biological study of potent and covalent HER-2 tyrosine kinase inhibitors with low cytotoxicity in vitro

The discovery and development of a novel HER-2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer are presented in this article. EGFR family has been recognized as a crucial meditator in the cancer progression; HER-2 tyrosine kinase was one of the members among them. In the effort to explore potent HER-2 inhibitors, a novel series of 4-anilino-3-cyanoquinoline derivatives have been designed, synthesized and evaluated. Most compounds possessed modest proliferation inhibition on SK-BR-3 cell line and HER-2 kinase. Compound 16 appeared to be the most potent compound (HER-2 kinase IC50: 19.4?nM, SK-BR-3 IC50: 94?nM). In the experiment of cellular cytotoxicity assay, compound 16 shows a much lower cytotoxicity than neratinib on Beas-2b cell line (Human bronchial epithelial cells). In conclusion, compound 16 would be a promising lead compound for further anti-breast cancer drug discovery.

Preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and preparation method of bosutinib

The invention provides a preparation method of a disubstituted 4-chloroquinoline-3-carbonitrile derivative and a preparation method of bosutinib. The preparation method of the disubstituted 4-chloroquinoline-3-carbonitrile derivative comprises the following steps: disubstituted o-nitrobenzoate (II) used as a raw material and acetonitrile are condensed under the action of an alkali to obtain a compound of formula III; the compound of formula III and a chloroformylating reagent undergo a chloroformylating reaction to obtain a compound of formula IV1 or formula IV2; and the compound of formula IV1 undergoes catalytic hydrogenation cyclization in the presence of a hydrogenation catalyst to prepare 7-[3-(4-methyl-1-piperazinyl)propoxy]-6-methoxy-4-chloroquinoline-3-carbonitrile (Ia), or the compound of formula IV2 is subjected to catalytic hydrogenation cyclization and anhydride amidation to prepare 6-acetamido-7-ethoxy-4-chloroquinolin-3-carbonitrile (Ib). The compound of formula Ia or Ibis used to prepare bosutinib, neratinib or pelitinib. The method of the invention has the advantages of short process flow, simplicity in operation, easiness in realization, low cost, few three wastes, high yield, high purity, and easiness in industrial production.

Clean production method of antitumor drug pelitinib intermediate

The invention belongs to the technical field of preparation of new drugs, and particularly relates to a clean production method of an antitumor drug pelitinib intermediate. According to the present invention, 3-cyano-4-hydroxy-6-acetamido-7-ethoxyquinoline is chlorinated by using phosphorus oxychloride as a chlorinating reagent and using an aromatic ring solvent under the catalysis of imidazoliumiodide to prepare the antitumor drug pelitinib intermediate 3-cyano-4-chloro-6-acetamido-7-ethoxyquinoline; and with the method, the consumption of phosphorus oxychloride is substantially reduced, wherein the good reaction conversion can be achieved only with 2.0 eq of phosphorus oxychloride so as to reduce the environmental protection pressure and improve the quality and the yield of the product.

Preparation method of Neratinib intermediate

The invention relates to the field of chemical synthesis, and specifically relates to a preparation method of a Neratinib intermediate. A compound (I) is taken as the raw material, and through a series of reactions, the intermediate compound (VIII) of a novel antitumor drug Neratinib is obtained. A high efficient synthesis route is provided and has the characteristics of low cost, few byproducts, high yield, and little environmental pollution.

Preparation method of Neratinib intermediate

The invention discloses a preparation method of a Neratinib intermediate. The preparation method comprises the following steps: by taking a compound A and POCl3 as raw materials, and a nitrogenous compound as a catalyst, allowing the compound A and POCl3 to react with the nitrogenous compound to obtain the Neratinib intermediate, wherein the compound A is (E)-N-(4-((2-cyano-3-morpholino-3-oxopropionic-1-alky-1-base)amino)-2-ethoxy phenyl) acetamide. According to the method, the nitrogenous compound is used as the catalyst, high temperature is not needed in the reaction, the reaction can be performed at the temperature of 65 to 75 DEG C, compared with the traditional method requiring the high temperature of 200 to 250 DEG C, the reaction temperature is greatly reduced, the high-temperature reaction is avoided, operation safety is ensured, the reaction yield is also increased to 45 to 57 percent, and the yield is obviously increased.

New synthesis of N-(4-chloro-3-cyano-7-ethoxyquinolin- 6-yl)acetamide

New synthetic route of N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)- acetamide (1) is described on a hectogram scale. The key steps include the intramolecular cyclization of 3-amino-2-(2-chlorobenzoyl)acrylonitrile 22 to give the 3-cyano-4-quinolone 7, which was chlorinated by POCl3 to give the final product 1 in 36.9% yield over 9 steps and 98.9% purity (HPLC). Purification methods of 7 and 1 were also given.

A new and improved process for N -(4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide

A new and improved synthetic route to N-(4-chloro-3-cyano-7-ethoxyquinolin- 6-yl)acetamide (1) is described on a kilogram scale. The key step is the basic cyclization of o-[(2-cyanovinyl)amino]benzoate (14) in tBuONa/ tBuOH system to give the 3-cyano-4-hydroxyquinoline (7). The final product 1 is obtained with 49% overall yield (seven steps) and 98.9% purity (HPLC), which makes it a cost-effective and commercially friendly process for scale-up operations.

Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides

Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6- yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

PREPARATION METHODS OF 6-SUBSTITUTED AMINO-3-CYANOQUINOLINE COMPOUNDS AND THE INTERMEDIATES THEREOF

The present invention relates to a method for preparing 6-substituted amino-3-cyanoquinoline compounds (compound A for short) and the intermediates thereof, more particularly, to a compound of the following formula (I), the preparation method thereof, the intermediates thereof and use thereof for preparing the compound A. The compound of the formula (I) is cyclized in the presence of an alkali to give a compound of formula A, wherein W is OH; or the compound of the formula (I) is cyclized in the presence of an alkali, and then chlorinated to give a compound of the formula A, wherein W is Cl. Compared with the known methods in the literature, the method for preparing the compound A from the compound of formula (I) according to the present invention can avoid using high-temperature condition and high boiling point solvents, and is safe and environment-friendly, mild in reaction condition, easy in operation with a high yield and high product purity.