FIELD Olr THE INVENTION:

The present invention relates to novel synthesis o!' (E)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1 -yl)acetamido)phenyl)amino)(phenyl)melhylene)-2-oxo-2 ,3-dihvdro-1 H-pyrrolo[2,3-b]pyridine-6-carboxylate
BACKGROUND OF THE INVENTION:

(E)-melhyl-3-{((4-(N-iuethyl-2-(4-methylpiperazin-1 -yl)acetamido)phenyl)amino)(phenyl) methylene)-2-oxo-2.3-dihydro-1 H-pyrrolo[2.3-b]pyridine-6-carboxylate is the chemical name oi' the drug being developed by Angion Biomedica Corp is a highly selective, oral small molecule tyrosine kinase receptor inhibitor developed internally as a potential treatment lor chronic fibrotic diseases, particularly in the kidney and lung. 'I'llis is also known as ANG-3070.
IN 6869/DELNP/2014 assigned to Angion Biomedica Corp. discloses and claims the compound ANG-3070 and a process For preparing the same.
WO 2022/006238 A! assigned to Angion Biomedica Corp, discloses crystalline solid forms Form A. Form B. Form C, Form D. Form E. Form F. Form G and Form H pharmaceutical compositions comprising the same, and methods of use (hereof.

The present invention provides a process for the preparation of(E)-melhyl-3-(((4-(N-melhyl-2-(4-methylpiperazin-1 -yl)acetamido)phenyI)amino)(phenyl) methylenc)-2-oxo-2.3-dihvdro-1 H-pyrrolo[2,3-b]pyridine-6-carboxylate. which is industrially viable.

OBJECTIVE OF THE INVENTION:

The main object of the present invention is to provide a process for the preparation of(E)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-1 -yl)acetamido)phenyl)amino)(phcnyl) methvlene)-2-oxo-2,3-dihydro-1 H-pyrrolo| 2,3-b]py rid ine-6-carboxy late

S U M M A R V O F T H E i N VE NT ION:

The main aspect of the present invention is to provide a novel Process for the preparation of (E)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-vljacetamido) pheny])amino) (phenyl) methylene)-2-oxo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-6-carboxylate and its

pharmaceutically acceptable salts, which comprises the following steps:

1) methyl 2-o.xo-2,3-dihvdro-1 H-pyrrolo[2.3-b] pyridine-6-carboxylaie (Compound 2) reacted with methyl benzoate in alcohol solvent in reflux condition using catalyst,
2) (E)-methyl 3-benzylidene-2,3-dihydro-2-oxo-1 H-pyrrolo[2.3-bjpyridine-6-

carboxylate (compound 3) is brominated in presence of a solvent,
3) methyl 3-(bromo(phenyl)methyl)-2.3-dihydro-2-oxo-1 H-pyrrolo[2,3-b)pyridine-6-carboxylate (Compound 4) is condensed with N-(4-aminophenyl)-N-methyl-2-(l-methylpiperidin-4-yl)acetamide (Compound 5) in presence of alcohol.
DETAILED DESCRIPTION OF THE INVENTfON:

The present invention relates to a novel Process lor the preparation of (E)-methyl 3-({(4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido) phenyljamino) (phenyl) methylcnc)-2-oxo-2.3-dihydro-1 H-pyrrolo[2.3-b]pyridine-6-carboxylate and its pharmaceutically acceptable salts, which comprises the following steps:
1) methyl 2-oxo-2.3-dihydro-1 H-pyrroio[2.3-bj pyiidine-6-Ciirboxy];ue (Compound 2) reacted with methyl benzoate in alcohol solvent in rellux condition using catalyst,
2) (E)-methyl 3-benzylidcne-2.3-dihydro-2-oxo-1H-pyrrolo(2.3-b]pyridine-6-

carboxylate (compound 3) is brominaied in presence of a solvent.
3) methyl 3-(bromo(phenyl)methyl)-2.3-dihydro-2-oxo-1 H-pyrrolo[2.3-b]pyridine-6-carboxylate (Compound 4) is condensed with N-(4-aminophenyl)-N-meihyl-2-(l-methylpiperidin-4-yl)acetamide (Compound 5) in presence of alcohol.
According to the first embodiment of the present invention, the bromination is carried out using the brominating agent and a base.

According to the second embodiment of the present invention, catalyst is selected from the group of piperazine, pyridine or Piperdinc.

According to other embodiment of the present invention the solvent used is selected from the group of Methanol, ethanol. Isopropanol, butanol or mixture thereof, preferably Methanol

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non- limiting examples.

EXAMPLES:

Example -1: Preparation of Compound No:03:
100 gm of methyl 2-oxo-2,3-dihydro-1 H-pyrrolo[2.3-b] pyridine-6-carboxylate (Compound 2), 50 methanol was added into flask, 60 gm of benzaldehyde. 10 ml of piperdine was added and the mixture was healed 60-65°C. After the reaction die reaction mixture was cooled, and the precipitate was filtered. The filler cake was washed with methanol and dried to obtain 137 gm of (E)-methyl 3-benzylidene-2,3-dihydro-2-oxo-lH-pyrrolo[2,3-b]pyridine-6-carboxy!atc (compound 3) as a light brown solid yield-93.83% .
Example - 2: Preparation of Compound No:4:
100 gni of (E)-methyl 3-bcnzylidcne-2,3-dihydro-2-oxo-1 H-pyrrolo[2]3-bjpyridinc-6-carboxvlate (compound 3). dichloromeihane was added to a reaction flask, cooled. 3.0 gin of bromine was added dropwise. After the completion of the reaction, the reaction mixture was washed once with water and methylene dichloride layer was evaporated to dryness, and then add ethyl ether, filtered, and dried to obtain 100 g of methyl 3-(bromo(phenyl)methyl)-2.3-dihydro-2-oxo-1 H-pyrrolo[2:3-b]pyridine-6-carboxylate (Compound 4) as a yellow solid. yield:78.8%

Example-3: Preparation of Compound i\o:l
100 gm of methyl 3-(bromo(phenyl)methyl)-2.3-dihydro-2-oxo-l H-pyrrolo[2.3-b]pyridine-6-carboxylate (Compound 4). 7.5 gm of N-(4-aminophenyl)-N-melhyl-2-(I-methylpiperidin-4-yl)acetamide (Compound 5). ethanol and 50 grmof sodium hydrogen carbonate was added tova reaction flask, and after heating to reflux for 2 hour. Filter the inorganic compound and diStil of ethanol and cooled to 20°C. Water and dichloromethane added to reaction mass, layers separated and methylene dichloride layer was evaporated to dryness. Then I PA was added to the mass and precipitated material filtered, and dried to obtain (E)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-l -yl)acetamido) phenyl)amino) (phenyl) methylene)-2-o.\o-2.3-dihydro-I H-pyrrolo[2.3-b)pyridine-6-carboxylate yellow solid (Compound 1).