DESC:FIELD OF THE INVENTION

The present invention provides a novel intermediate of Adagrasib. The present invention also relates to the process for the preparation of Adagrasib or its salts thereof with high yield, reduced steps and commercially viable.

BACKGROUND OF THE INVENTION

Adagrasib (KRAZATI®) is an irreversible inhibitor of KRASG12C inhibitor, belongs to the RAS GTPase family. Adagrasib indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Studies on Adagrasib show that the medicine has long half-life, wide tissue distribution and good tolerance, and simultaneously.
Adagrasib is chemically known as 2- [(2S)-4-[7- (8-chloro-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2enoyl)piperazin-2-yl]acetonitrile. The chemical structure of Adagrasib is represented as formula I.

Preparation of Adagrasib is described in various patents and patent applications including the US Patent No. 1068937, US Patent application No. 20230357231, PCT applications WO2023039020, and WO2023205074. However, the prior art methods are not suitable for large scale manufacturing. In order to overcome the shortcomings of the synthetic processes described in the prior art, the present application aims to provide an improved process for preparing Adagrasib with high chiral purity, higher yield, commercially viable process capable of producing Adagrasib having better properties, such as physicochemical characteristics.

SUMMARY OF THE INVENTION

The present invention aims to provide a novel compound of formula V, compound of formula X and an improved process for preparing Adagrasib, in high yield and purity.
In an aspect, the present invention provides a compound of formula V or salt thereof,

In another aspect, the present invention relates to a process for the preparation of Adagrasib of compound of formula 1, or its pharmaceutically acceptable salts thereof,

comprising the steps of:
(a) reacting a compound of formula VIII or salt thereof with a compound of formula VII or salt thereof to obtain a compound of formula VI or salt thereof.

wherein Q is a leaving group and P is a protecting group,
(b) reacting a compound of formula VI or salt thereof, obtained in step (a) with an oxidizing agent to obtain a compound of formula V or salt thereof,

(c) reacting a compound of formula V or salt thereof, obtained in step (b) with (1-methylpyrrolidin-2-yl)methanol to obtain a compound of formula IV or salt thereof,

(d) deprotecting the compound of formula IV or its salt thereof obtained in step (c) to obtain a compound of formula III or salt thereof,

(e) converting compound of formula III or salt thereof to obtain Adagrasib, compound of formula I, or salt thereof.
In another aspect, the present invention provides compound of formula X or salt thereof, and its conversion to obtain to Adagrasib, compound of formula I, or salt thereof.

wherein P, R1, R2, Y, A are same as defined below.

DESCRIPTION OF THE INVENTION

In first aspect, the present invention provides a compound of formula V or salt thereof,

In second aspect, the present invention relates to a process for the preparation of Adagrasib, compound of formula I, or its pharmaceutically acceptable salts thereof,

comprising the steps of:
(a) reacting a compound of formula VIII or salt thereof with a compound of formula VII or salt thereof to obtain a compound of formula VI or salt thereof.

wherein Q is a leaving group and P is a protecting group,
(b) reacting a compound of formula VI or salt thereof, obtained in step (a) with an oxidizing agent to obtain a compound of formula V or salt thereof,

(c) reacting a compound of formula V or salt thereof, obtained in step (b) with (1-methylpyrrolidin-2-yl)methanol to obtain a compound of formula IV or salt thereof,

(d) deprotecting the compound of formula IV or salt thereof obtained in step (c) to obtain a compound of formula III or salt thereof,

(e) converting a compound of formula III or salt thereof obtained in step (d) to Adagrasib, compound of formula I, or salt thereof.
In third aspect, the present invention provides a compound of formula X or salt thereof,

Wherein Y is a bond, O, S, SO, SO2 or NR3;

each R3 is independently hydrogen or C1-C3 alkyl;

P is selected from hydroxy, alkoxy, C1-6 alkyl, aryl, alkyl sulfonyl, aryl sulfonyl, alkoxy carbonyl, carbonyl, heterocyclyl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl which are unsubstituted or substituted by substituents selected from the group consisting of C1-6 alkyl, hydroxyl, alkoxy, carboxyl, oxo group, halo, carbonyl, aryl, aryloxy, heteroaryl, and heterocyclyl;

R1 is hydrogen, alkyl, hydroxyalkyl, aryl, heteroaryl, or heteroarylalkyl;
A is a bond, -C(O)-, or C1 - C3 alkylene;

R2 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R4, R5 or R6.

R4 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R5;
each R5 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;
R6 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR3, —C(O)N(R3)2, —N(R3)2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, —OR3, —N(R3)2, or heteroaryl;
In fourth aspect, the present invention provides converting a compound of formula X or salt thereof, to obtain to Adagrasib, compound of formula I, or salt thereof.

wherein P, R1, R2, Y, A are same as defined above.

The term “P is intended to mean an amino protecting group selected from the group comprising from methyl sulfonyl, ethyl sulfonyl, p-toluene sulfonyl, p-nitrobenzene sulfonyl, Trifluoromethanesulfonyl (triflate), tert-Butyloxycarbonyl (Boc), Carboxybenzyl (Cbz), (2-(Trimethylsilyl)ethoxymethyl (SEM), Pivaloyloxymethyl (POM) and the like.

The term “Q is intended to mean a leaving group selected from the group comprising from halogen, selected from chlorine, iodine, bromide and the like; alkanesulfonyloxys, selected from methanesulfonyloxy, ethanesulfonyloxy and the like; arenesulfonyloxys, selected from benzylsulfonyloxy, tosyloxy, p-nitrobenzene sulfonyloxy and the like; thienyloxy, dihalophospbinoyloxy, tetrahalophosphaoxy, perfluoroalkanesulfonyloxys, selected from trifluoromethanesulfonyloxy and the like.

“Oxidizing agent” selected from the group comprising of meta-Chloroperbenzoic acid (mCPBA), osmiumtetroxide, hydrogenperoxide, potassium permanganate, magnesium chlorate, Silver chlorate, peroxymonosulfuric acid, Peracetic acid, Dimethyl dioxirane, sodium perborate, Nitrous oxide, Sodium hypochlorite, peroxy acetic acid, pyridinium chloroformate, pyridinium dichromate, chromium trioxide, TEMPO, TPAP, potassium dichromate and the like.

Schematic representation of route of synthesis of Adagrasib:

Representative Example:

1. Preparation of compound of formula G:
Compound of formula F is treated with 1,1-Dimethylethyl 2-(cyanomethyl)-1-piperazinecarboxylate to obtain compound of formula G.

2. Preparation of compound of formula H:
Compound of formula G is oxidised to obtain compound of formula H.

3. Preparation of compound of formula J:
Compound of formula H is treated with 1-Methyl-2-pyrrolidinemethanol to obtain compound of formula J.

4. Preparation of compound of formula K:
Compound of formula J undergo deprotection to obtain compound of formula K.

5. Preparation of compound of formula I:
Compound of formula K is converted to obtain compound of formula I.
,CLAIMS:WE CLAIM:
1. A novel Intermediate compound of Formula V or its salt thereof,

Wherein P is alkoxy carbonyl.
2. A process for preparing compound of Formula V or its salt thereof,
comprising the following steps:

a) Reacting a compound of Formula VIII:

wherein Q is a Leaving group,

with compound of Formula VII or its salt thereof:

wherein P is a protecting group,
to obtain a final compound of step (a) with the following structure:

b) Reacting the final compound of step (a) with an oxidizing agent to produce a final compound of step (b) with the following structure:

3. A use of compound of Formula V or its salt thereof, for preparing adagrasib
4. A process for preparing Adagrasib of compound of formula I, or its pharmaceutically acceptable salts, comprising the following steps:

b) Reacting a compound of Formula VIII:

wherein Q is a Leaving group,

with compound of Formula VII or its salt thereof:

wherein P is a protecting group,

to obtain a final compound of step (a) with the following structure:

b) Reacting the final compound of step (a) with an oxidizing agent to produce a final compound of step (b) with the following structure:

c) Reacting the final compound of step (b) with (1-methylpyrrolidin-2- yl)methanol to produce a final compound of step (c) with the following structure::

d) Reacting the final compound of step (c) with Methanolic HCl to remove the protecting group from the final compound of step (c) to produce a final compound of step (d) with the following structure:

e) converting a compound of formula III or its salt thereof obtained in step (d) in the presence of 2-fluoroprop-2-enoic acid to form Adagrasib, compound of formula I, or its salt thereof.

Dated this 04th day of March 2025