FIELD OF THE INVENTION:
The present invention relates to novel synthesis of (E)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2)3-dihydro-l H-pyrrolo[2.3-b]pyridine-6-carboxylate
Z 0
Formula-1
BACKGROUND OF THE INVENTION:
(E)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido)phenyl)amino)(phenyl) mcthylene)-2-oxo-2.3-dihydro-1 H-pyrrolo[2.3-b]pyridine-6-carboxylatc is the chemical name of 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 for chronic fibrotic diseases, particularly in the kidney and lung. This is also known as ANG-3070.
t / T'NH
1 o
Formula-1
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 Al 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 thereof.
The present invention provides a process for the preparation of (E)-methyl-3-(((4-(N-methyl-2-(4-melhylpiperazin-l -yl)acetamido)phenyl)amino)(phenyl) methylene)-2-oxo-2,3-dihydro-I 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-l-yl)acetamido)phenyl)amino)(phenyl) methylene)-2-oxo-2,3-di hydro-1 H-pyrrolo[2,3-b]pyridine-6-carboxylate
SUMMARY OF THE INVENTION:
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-l -yl)acetamido) phenyl)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-oxo-2.3-dihydro-1l-l-pyrrolo[2,3-b] pyridine-6-carboxylate (Compound 2) reacted with methyl benzoate in alcohol solvent in reflux condition using catalyst,
°yh O cr>o A Ax
m i Xx>=0
O H ---------------------- Y'N H
Solvent ®
Cum pound No:2 Compound No: J
2) (E)-methyl 3-benzylidene-2,3-dihydro-2-oxo-l H-pyrrolo[2,3-b]pyridine-6-
carboxylate (compound 3) is brominated in presence of a solvent, 3) methyl 3-(bromo(phenyl)melhyl)-2.3-dihydro-2-o.xo-1 H-pyrrolo[2.3-b]pyridine-6-carboxylate (Compound 4) is condensed with N-(4-aminophenyl)-N-methyl-2-{ 1 -methylpiperidin-4-yl)acetamide (Compound 5) in presence of alcohol.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a novel Process for the preparation of (E)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido) phenyl)amino) (phenyl) methylene)-2-oxo-2.3-dihydro-1 H-pyrrolo|2.3-b)pvridine-6-carboxvlatc and its pharmaceutically acceptable salts, which comprises the following steps:
1) methyl 2-oxo-2,3-dihydro-l H-pyrrolo[2,3-b] pyridine-6-carboxylate (Compound 2) reacted with methyl benzoate in alcohol solvent in reflux condition using catalyst,
°^h r
O i rv>=o
o ------------Y N H
Solvent O
Compound No:2 Compound No:3
2) (E)-methyl 3-benzylidene-2,3-dihydro-2-oxo-1 H-pyrrolo[2,3-b]pyridine-6-
carboxylate (compound 3) is brominated in presence of a solvent,
3) methyl 3-(bromo(phenyl)methyl)-2,3-dihydro-2-oxo-1 H-pyrro!o[2,3-b]pyridine-6-carboxylate (Compound 4) is condensed with N-(4-aniinophenyl)-N-methyl-2-( I-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 Piperdine.
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 he 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:
r.\:i 111 nlr -1 r Prrnii r;i tinn nf Cnm nnii nd Nndtt-
100 gm of methyl 2-oxo-2,3-dihydro-l 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 heated 60-65°C. After the reaction the reaction mixture was cooled, and the precipitate was filtered. The filter cake was washed with methanol and dried to obtain 137 gin of (E)-methvl 3-benzylidene-2.3-dihydro-2-oxo-l H-pyrrolo| 2.3-h|pyridine-6-carb<>x \ late (compound 3) as a light brown solid yield-93.83% .
100 gm of (E)-methyl 3-benzylidene-2,3-dihydro-2-oxo-l H-pyrrolo[2,3-b]pyridine-6-carboxylate (compound 3), dichloromethane was added to a reaction flask, cooled. 5.0 gm 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-l H-pyrrolo[2.3-b]pyridine-6-carboxylate (Compound 4) as a yellow solid. yield:78.8%
I UU gm or methyl 3-(broino(phenyl)methyl)-2J-dihydro-2-oxo-l H-pyrrolo[2 J-bjpyridine-b-carboxylate (Compound 4), 7.5 gm of N-(4-aminophenyl)-N-methyl-2-( 1-methylpiperidin-4-yl)aceiamide (Compound 5). ethanol and 50 urinof sodium hvdrouen carbonate was added io a reaction flask, and alter 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 1PA 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-oxo-2,3-dihydro-I H-pyrrolo[2.3-b]pyridine-6-carboxylale yellow solid (Compound 1).
We Claim:
I. A novel process for the preparation of (E)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-I-yl)acetamido) phenyl)amino) (phenyl) methylene)-2-oxo-2,3-dihydro-l H-pyrrolo[2,3-b]pyridine-6-carboxylate and its pharmaceutically acceptable salts, which comprises the following steps:
I) methyl 2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b] pyridine-6-carboxylate (Compound 2) reacted with methyl benzoate in alcohol solvent in reflux condition using catalyst,
2) (E)-methyl 3-benzylidene-2,3-dihydro-2-oxo-l H-pyrrolo[2,3-b]pyridine-6-
carboxylate (compound 3) is brominated in presence of a solvent.
3) methyl 3-(bromo(phenyl)methyl)-2.3-dihydro-2-oxo-l 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.
2. The process according to claim I. solvent is selected from the group of Methanol, ethanol. Isopropanol, or mixture thereof, preferably Methanol.
3. The process according to claim 1, catalyst is selected from the group of piperazine, pyridine or Piperdine.
3. The process according to claim I, alcohol is selected from the group of Methanol, ethanol. Isopropanol, butanol or mixture thereof, preferably Methanol.