262368-30-9

Basic information

• Product Name: N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide
• Synonyms: N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide;N-(4-Aminophenyl)-N,4-dimethyl-1-piperazineacetamide;N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine;-N-methyl-2-(4-methylpiperazin-1-yl);Nintedanib Intermediate 2
• CAS NO: 262368-30-9
• Molecular Formula: C₁₄H₂₂N₄O
• Molecular Weight: 262
• EINECS: 919-251-0
• Product Categories: Intermediate of BIBF-1120 and PKI587
• Mol File: 262368-30-9.mol

Chemical Properties

• Melting Point: 148-150
• Boiling Point: 434.8±40.0 °C(Predicted)
• Appearance: /
• Density: 1.151
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 7.43±0.10(Predicted)
• CAS DataBase Reference: N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide(262368-30-9)
• EPA Substance Registry System: N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide(262368-30-9)

Safety Data

• Hazardous Substances Data: 262368-30-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide is used as a reagent for the preparation of deuterated derivatives of nintedanib, a drug with angiokinase inhibitory, antitumor activity, and pharmacokinetic properties. The incorporation of deuterium into the molecular structure of nintedanib can potentially enhance its stability, bioavailability, and therapeutic efficacy, making it a valuable tool in the development of improved pharmaceutical agents.

Upstream product

• 1139453-98-7 N-methyl-2-(4-methylpiperazin-1-yl)-N-(4-nitrophenyl)-acetamide 
• 109-01-3 1-methyl-piperazine 
• 2653-16-9 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide 
• 79-04-9 chloroacetyl chloride 
• 100-15-2 N-methyl(p-nitroaniline) 
• 350-46-9 4-Fluoronitrobenzene 
• 74-89-5 methylamine 
• 586-78-7 para-nitrophenyl bromide 

Downstream Products

• 656247-17-5 nintedanib 
• 1448874-98-3 (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate 
• 1448875-01-1 (Z)-methyl 1-acetyl-3-((4-(N-methyl-2-(4-methylpiperazin-1-yl) acetamido)phenylamino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate 
• 1448874-96-1 (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate 
• 262366-32-5 (Z)-N-methyl-2-(4-methylpiperazin-1-yl)-N-(4-(((2-oxoindolin-3-ylidene)(phenyl)methyl)amino)phenyl)acetamide 
• 894783-71-2 BIBF 1202 

Relevant articles and documents

Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction

A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitor

Refining method of amino intermediate

The invention relates to a tefining method of an amino intermediate represented by formula (I). Through the refining method, the concentrations of a genotoxic impurity 1 (N-(4-nitrophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide) and an impurity 2 (N-(4-(hydroxyamino) phenyl)-N-methyl-2- (4-methylpiperazin-1-yl) acetamide) can be controlled to 4 ppm or less. According to the present invention, the contents of the genotoxic impurity 1 and the genotoxic impurity 2 in the formula (I) are significantly reduced, such that the process guarantee is provided for the industrial preparation of high-quality nintedanib ethanesulfonate, and the medication safety is ensured.

Preparation method of nintedanib key intermediate

The invention provides a preparation method of a nintedanib key intermediate, and belongs to the technical field of synthesis of medical intermediates. The first preparation method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking an alcohol reagent or tetrahydrofuran as a solvent, taking hydrazine hydrate as a reducing agent and taking palladium carbon (Pd/C) as a catalyst until the nitro reduction reaction is complete, performing filtering to remove the catalyst under the protection of nitrogen, performing desolventizing to remove the solvent, performing dissolving by using dichloromethane, performing filtering to remove impurities, and performing desolventizing to obtain a compound I; the second method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking hydrazine hydrate as a reducing agent and anhydrous ferric trichloride and activated carbon as catalysts until the nitro reduction reaction is complete, performing performing filtering to remove the catalyst, performing desolventizing to remove the solvent, dissolving dichloromethane, drying anhydrous sodium sulfate, performing filtering, and performing desolventizing to obtain a compound I. The preparation method provided by the invention is high in yield, strong in operability and high in safety, belongs to an environment-friendly process, and is suitable for industrial large-scale production.

Preparation method of amino intermediate (by machine translation)

Compared with an existing preparation method, the method for preparing. the amine-based (I) intermediate disclosed by the invention comprises the following, steps: carrying (III) out condensation, reduction and the like of the compound of. the formula I to obtain, the target compound (I), and 1 remarkably reducing the, content of the impurities in the obtained compound according to the, invention as compared with the existing preparation. method. (by machine translation)

Preparation method of nintedanib key intermediate

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a nintedanib key intermediate compound II. A compound IV is reduced by adopting a common reaction reagent under the conditions of normal temperature and normal pressure, so that a high-purity compound II can be conveniently obtained. The adopted reaction conditions are mild, high-pressure equipment is avoided, the technical operation is simple, the conditions are mild, the process is safer and more environmentally friendly, and the feasibility of large-scale productionof nintedanib is greatly improved.

INDOLINONE COMPOUNDS FOR USE AS MAP4K1 INHIBITORS

The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring C, X1, X2, L1, R1, R2, R3, R4, R5, R6, R7, m and n are as defined herein, which are useful as MAP4K1 inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by MAP4K1.

INDOLINONE DERIVATIVES AS INHIBITORS OF MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE

The present disclosure relates to indolinone compounds, compositions, and methods for the inhibition of maternal embryonic leucine zipper kinase (MELK). The present disclosure further relates to indolinone compounds, compositions, and methods for the treatment or prevention of a cancer (for example, triple negative breast cancer).

Method for preparing Nintedanib,I intermediate through one-pot method

The invention relates to a method for preparing Nintedanib,I key intermediate N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-group)acetamide through a one-pot method. The method comprises the steps that according to the technical scheme, N-methyl-4-nitroaniline is dissolved in an aqueous solution of an organic solvent and alkali, mixing is carried out, then chloroacetyl chloride or bromoacetyl bromide is dropwise added, and a first-stage reaction is carried out for 0.1-3 hours at the temperature of 0-70 DEG C; a water layer is removed, N-methyl piperazine is added, a second-stage reactionis carried out, and reacting is carried out for 2-10 hours at the temperature of 0-75 DEG C; then a reducing reagent is added, a third-stage reaction is carried out for 8-36 hours at the temperatureof 0-75 DEG C and the pressure of 15-100 psi. After the reaction is finished, filtering is carried out to remove the reducing reagent, the reaction liquid is condensed, a reverse phase solvent is added, crystallization is carried out, and the Nintedanib,I key intermediate N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-group)acetamide (formula B) is obtained. According to the preparation method, the raw materials are easy to obtain, the process is simple, and the method is economical, environmentally friendly and suitable for industrial production.

Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth

Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers.

Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018 were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses (q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent manner. The improved efficacy of KBP-7018 compared to nintedanib provided a certain level of chemical validation for the involvement of PDGFR, c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase inhibitor with differentiated activity, highly enhanced selectivity, and acceptable PK profiles that will enter phase I clinical trials.