656247-18-6

Usage

Uses

Used in Pulmonary Fibrosis Treatment:
Nintedanib Ethanesulfonate Salt is used as an antifibrotic agent for the treatment of idiopathic pulmonary fibrosis (IPF), a condition in which the lungs become progressively scarred over time. It was approved by the US FDA in October 2014 and by the EMA in January 2015.
Used in Cancer Therapy:
Nintedanib Ethanesulfonate Salt is used as an angiokinase inhibitor for cancer therapy. It inhibits the process of blood vessel formation, which is essential for tumor growth and metastasis. The drug was also approved by the EMA in November 2014 for the treatment of non-small cell lung cancer in combination with docetaxel after first-line chemotherapy.

Synthesis

The synthesis of indolinone 197 commenced with commercial 4-chloro-3-nitro-benzoic acid (194)—esterification of which preceded displacement of the chloride by dimethyl malonate (195) in the presence of base to generate nitrobenzene 196. Hydrogenation of 196 under acidic conditions furnished 6-methyoxycarbonyl- substituted oxindole 197 by decarboxylative cyclization in 87% yield. Acylation of indolinone 197 with chloroacetic anhydride in refluxing toluene and subsequent condensation with trimethyl orthobenzoate resulted in indolone 198, which was isolated in 86% yield over the two-step sequence. While these two steps could reportedly be combined into a one-pot protocol using acetic anhydride as the solvent, the stepwise procedure was found to be more amenable for large-scale synthesis due to fewer complications with undesired side products. Subjection of 198 to methanolic potassium hydroxide followed by condensation with aniline fragment 199 in refluxing methanol and then exposure to aqueous ethanesulfonic acid in methanol provided nintedanib esylate (XXIII) in 82% over the three-step sequence. Aniline fragment 199 was prepared in three steps and 82% overall yield via initial acylation of N-methyl-4-nitroaniline 200 with chloro acetylchloride followed by displacement of the a-amidochloride with N-methylpiperazine and hydrogenative reduction of the nitro group gave the desired aniline.183,184

Upstream product

• 656247-17-5 nintedanib 
• 594-45-6 ethanesulfonic acid 
• 855860-75-2 N-(4-aminophenyl)-2-chloro-N-methylacetamide 
• 2653-16-9 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide 
• 98-88-4 benzoyl chloride 
• 2093243-16-2 methyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate 
• 1139453-98-7 N-methyl-2-(4-methylpiperazin-1-yl)-N-(4-nitrophenyl)-acetamide 
• 109-01-3 1-methyl-piperazine 
• 1663-61-2 triethoxymethylbenzene 
• 1168152-06-4 (E)-1-acetyl-3-(ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 676326-36-6 1-acetyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 100-44-7 benzyl chloride 
• 2093243-16-2 methyl 3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate 
• 1160293-25-3 methyl 1-(2-chloroacetyl)-2-oxoindoline-6-carboxylate 

Downstream Products

• 656247-17-5 nintedanib 

Relevant academic research and scientific papers

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 of novel crystal form I of nintedanib ethanesulfonate salt

The invention belongs to the technical field of chemical crystallization of medicines, and particularly relates to a nintedanib ethanesulfonate salt crystal form I. The X-ray powder diffraction 2[theta] diffraction angle of the crystal form I has characteristic absorption peaks at the positions of 5.869, 7.674, 8.744, 9.781, 11.005, 11.702, 13.255, 13.936, 14.175, 15.897, 16.445, 16.645, 17.646, 17.979, 18.785, 19.145, 19.644, 20.064, 21.519, 22.255, 23.256, 23.578, 23.929, 25.149, 25.515, 26.741, 27.221, 28.197, 28.584, 28.945, 30.662, 31.537 and the like, and the error of 2[theta] is 0.2 degree. The invention provides four preparation methods of the crystal form I. The crystal form I is relatively high in purity and relatively good in stability.

Method for preparing nintedanib ethanesulfonate

The invention discloses a method for preparing nintedanib ethanesulfonate. The method comprises the following steps: carrying out acylation reaction on 2-oxoindole-6-methyl formate and acetic anhydride to obtain 1-acetyl-2-oxoindoline -6-methyl formate; condensing with trimethyl orthobenzoate to generate 1-acetyl-3-(methoxyphenyl methylene)-2-oxoindoline-6-methyl formate, and finally reacting withN-(4-aminophenyl)-N, 4-dimethyl-1-piperazinecarboxamide; under the condition of not separating a main product, adding an alkali for deprotection to generate nintedanib, and finally salifying with ethanesulfonic acid to generate the nintedanib ethanesulfonate. The method has the advantages of mild reaction conditions, simple process operation and high yield, can obtain the nintedanib ethanesulfonate with the purity of 100% without refining, and is suitable for industrial production.

Preparation method of high-purity nintedanib ethanesulfonate

The invention discloses a preparation method of high-purity nintedanib ethanesulfonate, which comprises the following steps: 1, carrying out one-pot reaction on toluene, SM01, triethyl orthobenzoate,acetic anhydride and DMAP, and carrying out suction filtration to obtain a high-purity intermediate INT02; 2, reacting INT02 and SM02 in a specific solvent system and then separating to obtain an intermediate INT03; 3, enabling INT03, methanol and KOH to react to obtain INT04; 4, reacting INT04, methyl alcohol and ethanesulfonic acid, adding methyl tert-butyl ether and isopropyl ether to obtain nintedanib ethanesulfonate.

SYNTHESIS OF A 2-INDOLINONE DERIVATIVE KNOWN AS INTERMEDIATE FOR PREPARING NINTEDANIB

The invention discloses the preparation method of methyl (E)-1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindoline-6-carboxylatefrom methyl 2-oxoindoline-6-carboxylate using high reaction temperatures and a reaction solvent enabling azeotropic removal of acetic acid during the reaction.

Method for preparing Nintedanib ethylsulfonate

The invention relates to a method for preparing Nintedanib ethylsulfonate. The method comprises the following steps: (1) adding 1-acetyl-3-[methoxy(phenyl)methylene]-2-oxo-indolinyl-6-methyl formate (compound A) into a reaction solvent to react with N-(4-amino phenyl)-N,4-dimethyl-1-piperazinyl acetamide (compound B), adding pyrrolidine for continuous reaction after the reaction ends up, carryingout crystallization, carrying out stirring washing with a mixed solvent, and carrying out drying, so as to produce (3Z)-3-{[(4-{methyl-[(4-methyl piperazin-1-yl)acetyl]amino}phenyl)amino]-(phenyl)methylene} -2-oxo-2,3-indolinyl-6-methyl formate (compound C); and (2) subjecting the compound C to a reaction with ethyl sulfonic acid, carrying out crystallization, carrying out filtering, and carryingout drying, thereby producing the Nintedanib ethylsulfonate. According to the method, the Nintedanib ethylsulfonate with high purity, good yield and low impurity level is obtained through reactions oftwo steps.

An improved process for the synthesis of nintedanib esylate

Nintedanib esylate is synthesized via novel intermediates of (Z)-methyl 3-(acetoxy-phenyl)methylene)-1-acetyl-2-oxoindoline-6-carboxylate and N-(4-aminophenyl)-2-chloro-N-methylacetamide in good yields.

One-pot synthesis method of preparing nepal reaches Neeb

The invention discloses a method for preparing Nintedanib through a one-pot process. The method comprises the following steps: taking 2-oxyindole-6-methyl carbonate, methyl benzoate and N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-yl) acetamide as initial raw materials, carrying out an alpha-hydrogen substitution reaction between 2-oxyindole-6-methyl carbonate and methyl benzoate in the presence of an inorganic base, and docking with N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-yl) acetamide. The preparation method is simple, feasible, high in yield, high in quality and convenient for industrial production.

nepal reaches the Neeb second grade sulfonic acid hydrate pharmaceutical new crystal (by machine translation)

The invention of nepal reaches the Neeb second grade sulfonate monohydrate crystalline form A using Rigaku Smartlab - 3 type X - ray diffractometer, in CuK - of beta, 40 kv, measured under the conditions of the measuring 30 mA X - ray diffraction diagram has included in the diffraction angle 2 θ: 11.554 degrees, 17.423 degrees, 18.800 degrees, 19.683 degrees, 19.986 degrees of diffraction peaks, 2 θ error is 0.2 degrees. The inventors of the nepal reaches the Neeb second grade sulfonate monohydrate crystalline form simple preparation process, high purity and good stability. (by machine translation)

Preparation method of crystalline nintedanib esylate

The invention discloses a preparation method of crystalline nintedanib esylate (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-dihydroindolone monoethyl sulfonate). The method comprises steps as follows: (1) a compound represented in the formula (B) and acylating chlorination reagent chloroacetic anhydride react, and acyl chloride (C) is obtained; (2) the compound represented in the formula (C) and trimethyl orthobenzoate have a condensation reaction, and a compound represented in the formula (D) is obtained; (3) the compound represented in the formula (D) is deprotected, and a compound represented in the formula (E) is obtained; (4) the compound represented in the formula (E) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide have a condensation reaction, and a compound represented in the formula (F) is obtained; (5) the compound represented in the formula (F) and ethanesulfonic acid have a salification reaction, and a nintedanib esylate compound represented in the formula (A) is obtained. The stable crystalline nintedanib esylate can be obtained with the method, technological conditions are mild, aftertreatment is simple, the purity is high, the reaction cost is low, and industrial production is easy to realize.