DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR PREPARATION OF ADAGRASIB AND ITS INTERMEDIATES
INTRODUCTION
The present application relates to a process for preparation of Adagrasib (I) or its pharmaceutically acceptable salts thereof. The present application also relates to the process for preparation of intermediates or their pharmaceutically acceptable salts thereof, and their application in the preparation of Adagrasib (I).
Adagrasib is a KRAS inhibitor being developed by Mirati Therapeutics. It was approved in US under the brand name KRAZATI for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) as determined by an FDA approved test, who have received at least one prior systemic therapy. Adagrasib is chemically known as {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1- methylpyrrolidin-2-yl]methoxy}-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop2-enoyl)piperazin-2-yl}acetonitrile.
Adagrasib was first disclosed in WO2019099524A1 (hereinafter referred as the WO’524 application) assigned to Mirati Therapeutics. WO2023039020A (hereinafter referred as the WO’920 application), Org. Process Res. Dev. 2023, 27, 3, 530–538, Org. Lett. 2023, 25, 6, 944-949 and CN116675690A (hereinafter referred as the CN’690 application) also discloses various processes for preparation of Adagrasib and its intermediates. However, all these processes either employ transition metal catalysts for the key C–O bond formation step or involve the use of expensive reactants such as 2-alkylisothiouronium salts to construct the intermediate needed for this step. Hence, these routes are not suitable for commercial production of Adagrasib as they are difficult to handle at large scale and involve challenges in removing the residual metal impurities which cause undesired side reactions downstream.
Hence, there is a need for an improved and cost effective process for the commercial production of Adagarsib (I) or its pharmaceutically acceptable salts thereof.

SUMMARY
First aspect of the present application relates to a process for the preparation of Adagrasib (I) or its pharmaceutically acceptable salts thereof, comprising reacting compound of formula (II) with 2-fluoroacrylic anhydride or mixed anhydride of 2-fluoroacrylic acid to produce compound of formula (I) or its pharmaceutically acceptable salts thereof,
.
Second aspect of the present application relates to a process for preparation of compound of formula (VI) or its pharmaceutically acceptable salts thereof, comprising reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base to produce compound of formula (VI) or its pharmaceutically acceptable salts thereof,
.
wherein X is a halogen; P1 and P2 are same or different amino protecting groups.
Third aspect of the present application relates to a process for preparation of Adagrasib (I) comprising the following steps:
a) reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base to produce compound of formula (VI) or its pharmaceutically acceptable salts thereof,
;
b) deprotecting compound of formula (VI) in presence of a suitable reagent to provide compound of formula (V);
;
c) reacting compound of formula (V) with compound of formula (IV) to provide compound of formula (III) or salt thereof
;
d) deprotecting compound of formula (III) to compound of formula (II) or salt thereof in presence of a suitable reagent
;
e) reacting compound of formula (II) with 2-fluoroacrylic anhydride or mixed anhydride of 2-fluoroacrylic acid to produce compound of formula (I) or its pharmaceutically acceptable salts thereof,
;
Wherein P1 and P2 are same or different amino protecting groups.
Fourth aspect of the present application relates to a compound of formula (XII) and/or (XIIa).
.

Fifth aspect of the present application relates to a compound of formula (XI) and/or (XIa).

DETAILED DESCRIPTION
First aspect of the present application relates to the process for the preparation of compound of formula (I) or its pharmaceutically acceptable salts thereof, comprising reacting compound of formula (II) with 2-fluoroacrylic anhydride or a mixed anhydride of 2-fluoroacrylic acid to produce compound of formula (I) or its pharmaceutically acceptable salts thereof,
.
In one embodiment of present application, the compound of formula (I) obtained by reacting compound of formula (II) with 2-fluoroacrylic anhydride in a suitable solvent and optionally in presence of a suitable base. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; ; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof. Specifically, the solvent may be nitrile solvent. Suitable base may be an organic base or inorganic base. Inorganic base includes but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like. Organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine and the like. More specifically, acetonitrile. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature of about 5 °C to about 35 °C.

In another embodiment of present application, the compound of formula (I) obtained by reacting compound of formula (II) with a mixed anhydride of 2-fluoroacrylic acid.
Mixed anhydride of 2-fluoroacrylic acid may be prepared by reacting 2-fluoroacrylic acid with a second suitable acid or acid derivative in presence of a suitable base.
Second suitable acid or acid derivative includes but not limited to carboxylic acids or their derivatives such as pivalic acid or pivaloyl chloride; benzoic acid or their derivatives such as 2,4,6-trichlorobenzoic acid, 2,4,6-trichlorobenzoyl chloride; carbonic acid derivatives such as ethyl chloroformate and isobutyl chloroformate, Boc anhydride; boric acid; and sulfonic acids or their derivatives such as p-toluenesulfonic acid or p-toluenesulfonyl chloride and methanesulfonic acid or methanesulfonyl chloride; Specifically, the second suitable acid or acid derivative is 2,4,6-trichlorobenzoic acid, 2,4,6-trichlorobenzoyl chloride (2,4,6-tribromobenzoyl chloride).
Mixed anhydride of 2-fluoroacrylic acid may be generated in situ during the reaction.
Suitable base may be an organic base or inorganic base. Inorganic base includes but not limited to metal hydroxides such as such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like. Organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine, and the like, mixture thereof. Specifically, suitable base is selected from organic base. More specifically, base is TEA/DMAP. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof. Specifically, the solvent may be chlorinated solvent. More specifically, dichloromethane. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature of about 5 °C to about 35 °C.

Second aspect of the present application relates to a process for preparation of compound of formula (VI) or its pharmaceutically acceptable salts thereof, comprising reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base to produce compound of formula (VI) or its pharmaceutically acceptable salts thereof,
.
wherein X is a halogen; P1 and P2 are same or different protection groups.
In an embodiment, compound of formula (VI) is obtained by reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base and a suitable solvent to obtain compound of formula (VI). Suitable base may include but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; metal carbonates bases such as potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal fluorides such as sodium fluoride, potassium fluoride, cesium fluoride and the like; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) and the like; metal hydrides such as sodium hydride, potassium hydride and the like; organic bases such as triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine and the like. Specifically, suitable base is selected from metal alkoxides. More specifically, base is sodium t-butoxide. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran (2-MeTHF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; and mixtures thereof. Specifically, the solvent may be ether solvent. More specifically, tetrahydrofuran. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature of about 5 °C to about 75 °C.
In a further embodiment, the inventors of the present application, surprisingly found that the use of alkoxide base achieved better yield and purity compared to other processes/conditions reported in the literature. Details are given below:
S. No. Condition Purity (% by HPLC) of the crude material Purity (% by HPLC) after purification
1 Cs2CO3, RuPhos Pd G3 55 98
2 Sodium hydride (NaH) -- 78.7
3 NaOt-Am 85.22 95.5
4 NaOt-Bu 97 99

Specific aspect of the present application relates to a process for preparation of compound of formula (VIa) comprising reacting compound of formula (VIIIa) with compound of formula (VII) in presence of a suitable base in a suitable solvent to produce compound of formula (VIa)
.
Third aspect of the present application relates to a process for preparation of Adagrasib (I) comprising the following steps:
a) reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base to produce compound of formula (VI) or its pharmaceutically acceptable salts thereof,
;
b) deprotecting compound of formula (VI) in presence of a suitable reagent to provide compound of formula (V);
;
c) reacting compound of formula (V) with compound of formula (IV) to provide compound of formula (III)
;
d) deprotecting compound of formula (III) in presence of a suitable reagent to provide compound of formula (II)
;
e) reacting compound of formula (II) with 2-fluoroacrylic anhydride or a mixed anhydride of 2-fluoroacrylic acid to produce compound of formula (I) or its pharmaceutically acceptable salts thereof,
;
wherein P1 and P2 are same or different amino protecting groups.

In embodiments of step a) compound of formula (VI) is obtained by reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base in a suitable solvent to obtain compound of formula (VI). Suitable base may include but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; metal carbonates bases such as potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal fluorides such as sodium fluoride, potassium fluoride, cesium fluoride and the like; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) and the like; metal hydrides such as sodium hydride, potassium hydride and the like; organic bases such as triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine and the like. Specifically, suitable base is selected from metal alkoxides. More specifically, base is sodium t-butoxide. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran (2-MeTHF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; and mixtures thereof. Specifically, the solvent may be ether solvent. More specifically, tetrahydrofuran. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction of step a) may be carried out at a temperature of about 5 °C to about 75 °C.
In embodiments of step b) compound of formula (VI) is deprotected to compound of formula (V) in presence of a suitable regent in a suitable solvent. Suitable reagent may be including but not limited to Lewis acid such as BBr3, BCl3, AlCl3 and the like; Brønsted acid such as H2SO4, p-toluene sulfonic acid, trifluoroacetic acid (TFA) and the like; oxidants such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), ammonium cerium (IV) nitrate (CAN) and TEMPO the like; palladium catalyzed hydrogenation. Specifically, palladium catalyzed hydrogenation. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol, isopropanol (IPA) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran (2-MeTHF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water; and mixtures thereof. Specifically, the solvent may be alcohol solvent. More specifically, methanol. The reaction of step b) may be carried out at a temperature of about 20 °C to about boiling point of the solvent.
In embodiments of step b), isolation of compound of formula (V) may involve an optional step of salt formation using suitable acid. Suitable acid may include but not limited acetic acid, adipic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, hydrochloric acid, hydrobromic acid, lactic acid, malonic acid, methanesulfonic acid, oxalic acid, succinic acid, tartaric acid, trifluoroacetic acid and the like. Specifically, suitable acid is tartaric acid.
In embodiments of step b), isolation of compound of formula (V) can proceed with or without isolation of salt of compound of formula (V).
In embodiments of step c), reaction between compound of formula (IV) and compound of formula (V) is carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; ether solvent such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water and mixtures thereof. Specifically, the solvent may be aromatic hydrocarbon solvent. More specifically, the solvent is toluene. In embodiments of step c), reaction between compound of formula (IV) and compound of formula (V) may be carried out in presence of a suitable metal catalyst. The catalyst may be any catalyst known in the art. Specifically, the metal catalyst may be a palladium catalyst. More specifically, the palladium catalyst may be Palladium acetate [Pd(OAc)2]. In embodiments of step c), reaction between compound of formula (IV) and compound of formula (V) may further comprise the use of suitable ligand. The suitable ligand may be any ligand known in the art. Specifically, the ligand may be Xantphos. The reaction between compound of formula (IV) and compound of formula (V) may be carried out in presence of a suitable base. Suitable base may include but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as sodium methoxide, sodium t-butoxide and the like; metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal fluorides such as sodium fluoride, potassium fluoride, cesium fluoride and the like; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) and the like; metal hydrides such as sodium hydride, potassium hydride and the like; organic bases such as triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine and the like. Specifically, the base may be cesium carbonate. The reaction of step c) may be carried out at a temperature of about 20 °C to about boiling point of the solvent.
In embodiments of step d) deprotection of compound of formula (III) to compound of formula (II) is carried out in presence of a suitable reagent in a suitable solvent. Suitable solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; ether solvent such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be a ketone solvent. More specifically, the solvent is acetone. Suitable reagent used for the reaction of step d) may include but not limited to hydrochloric acid, hydrobromic acid, triflouroacetic acid, acetyl chloride, p-Toluenesulfonic acid, methanesulfonic acid and the like. Specifically, the suitable reagent may be p-Toluenesulfonic acid or Diluted or concentrated Hydrochloric acid, trifluoroacetic acid. The reaction of step d) may be carried out at a temperature of about 5 °C to about boiling point of the solvent.
In embodiments of step e), the compound of formula (I) obtained by reacting compound of formula (II) with 2-fluoroacrylic anhydride in a suitable solvent and optionally in presence of a suitable base. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; ; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof. Specifically, the solvent may be nitrile solvent. Suitable base may be an organic base or inorganic base. Inorganic base includes but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like. Organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine and the like. More specifically, acetonitrile. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature of about 5 °C to about 35 °C.
In embodiments of step e), the compound of formula (I) obtained by reacting compound of formula (II) with a mixed anhydride of 2-fluoroacrylic acid.
Mixed anhydride of 2-fluoroacrylic acid may be prepared by reacting 2-fluoroacrylic acid with a second suitable acid or acid derivative in presence of a suitable base.
Second suitable acid or acid derivative includes but not limited to carboxylic acids or their derivatives such as pivalic acid or pivaloyl chloride; benzoic acid or their derivatives such as 2,4,6-trichlorobenzoic acid, 2,4,6-trichlorobenzoyl chloride; carbonic acid derivatives such as ethyl chloroformate and isobutyl chloroformate, Boc anhydride; boric acid; and sulfonic acids or their derivatives such as p-toluenesulfonic acid or p-toluenesulfonyl chloride and methanesulfonic acid or methanesulfonyl chloride; Specifically, the second suitable acid or acid derivative is 2,4,6-trichlorobenzoic acid, 2,4,6-trichlorobenzoyl chloride.
Mixed anhydride of 2-fluoroacrylic acid may be generated in situ during the reaction.
Suitable base may be an organic base or inorganic base. Inorganic base includes but not limited to metal hydroxides such as such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like. Organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine, and the like, mixture thereof. Specifically, suitable base is selected from organic base. More specifically, base is TEA/DMAP. Suitable solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof. Specifically, the solvent may be chlorinated solvent. More specifically, dichloromethane. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature of about 5 °C to about 35 °C.
In further aspect, the process steps disclosed in the present application may be carried out in situ, without isolation of intermediates for preparation of compound of formula (I) and/or (II).

Specific aspect of the present application relates to a process for preparation of Adagrasib (I) comprising the following steps:
a) reacting compound of formula (VIIIa) with compound of formula (VII) in presence of a suitable base in a suitable solvent to obtain compound of formula (VIa)
;
b) converting compound of formula (VIa) to compound of formula (Va) in presence of a suitable regent;
;
c) reacting compound of formula (Va) with compound of formula (IV) to provide compound of formula (IIIa)
;
d) converting compound of formula (IIIa) to compound of formula (II) in presence of a suitable reagent
;
e) reacting compound of formula (II) with 2-fluoroacrylic anhydride or a mixed anhydride of 2-fluoroacrylic acid to provide compound of formula (I) or its pharmaceutically acceptable salts thereof,
.
In further embodiments, the compounds of formula (II) and/or (III) and/or (IIIa) and/or (V) and/or (Va) and/or (VI) and/or (VIa) are isolated as free form or pharmaceutically acceptable salts thereof.
In a specific aspect of the present application relates to a process for preparation of Adagrasib comprising reacting compound of formula (II) with 2-fluoroacrylic acid in presence of Yamaguchi reagent.

Fourth aspect of the present application related to a compound of formula (XII) and/or (XIIa).
.
In another aspect of the present application relates to a process for preparation of an acid addition salt of Adagrasib, comprising reacting adagrasib with a suitable acid.
Suitable acid includes but not limited to acetic acid, adipic acid, ascorbic acid, aspartatic acid, benzoic acid, camphorsulfonic acid, citric acid, formic acid, fumaric acid, HCl, HBr, HI, isethionic acid, lactic acid, malic acid, malonic acid, methanesufonic acid, nicotinicacid, nitric acid, oxalic acid, phosphoric acid, sulfuric acid, boric acid, succinic acid, tartaric acid, p-tolunesufonic acid, trifluoroacetic acid and their derivatives. Preferably, suitable acid is selected from tartaric acid or its derivative such as of tartaric acid, L-(+) tartaric acid, D-(-) tartaric acid, dibenzoyl-D-tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, and (-)-di-p-toluoyl-L-tartaric acid, (-)-dinitrobenzoyl-L-tartaric acid and (+)-dinitrobenzoyl-L-tartaric acid. More preferably, (-)-dibenzoyl-L-tartaric acid.

Fifth aspect of the present application related to a compound of formula (XI) and/or (XIa).
.
In another aspect of the present application relates to a process for preparation of an acid addition salt of compound of formula (II), comprising reacting compound of formula (II) with a suitable acid.
Suitable acid includes but not limited to acetic acid, adipic acid, ascorbic acid, aspartatic acid, benzoic acid, camphorsulfonic acid, citric acid, formic acid, fumaric acid, HCl, HBr, HI, isethionic acid, lactic acid, malic acid, malonic acid, methanesufonic acid, nicotinicacid, nitric acid, oxalic acid, phosphoric acid, sulfuric acid, boric acid, succinic acid, tartaric acid, p-tolunesufonic acid, trifluoroacetic acid and their derivatives. Preferably, suitable acid is selected from tartaric acid or its derivative such as of tartaric acid, L-(+) tartaric acid, D-(-) tartaric acid, dibenzoyl-D-tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, and (-)-di-p-toluoyl-L-tartaric acid, (-)-dinitrobenzoyl-L-tartaric acid and (+)-dinitrobenzoyl-L-tartaric acid. More preferably, tartaric acid.
Sixth aspect of the present application relates to a process for preparation of Adagrasib comprising converting one or more compounds selected from (XI), (XIa), (XII) and (XIIa) to Adagrasib.
Another aspect of the present application relates to a process for purification of compound of formula (II) from solvent system comprising IPA/water.
In further embodiments, the compounds of the present invention may be purified by any method known in the art such as chromatographic purification, crystallization, acid-base salt formation and the like using suitable solvents. Suitable solvent include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; alcohol solvent but not limited to methanol, ethanol, isopropanol and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof.
In another aspect relates to a continuous manufacturing of adagrasib is carried out in flow reactors. A flow reactor is a system through which the reactants are continuously pumped and product continuously collected. It is typically a device containing microchannels, static mixers or dynamic mixers which aids in enhanced heat and mass transfer properties. Further the reactors can be divided into static and dynamic mixing reactors, where the static reactors do not have any moving parts whereas the dynamic reactors have moving parts. The narrow channels in the reactors result in enhanced mixing resulting in near-plug flow conditions, thereby removing the mass transfer limitation typically associated with batch reactors. The flow reactors are built to withstand high temperature and pressure conditions, thus allowing for exploration and execution of novel process windows which require operation at high temperatures. The reactors are also small in size, occupying less footprint and allowing for operating flexibility. The three consecutive reactions are achieved in one single flow in Plug Flow reactors. The residence time of all three reactions in the PFR reactor is typically anywhere between 5 seconds and 15 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between 0°C and 100°C, preferably between 30°C and 60°C. Flow reaction are performed using PFR with or without static elements.
The advantages of the continuous process presented in the current application involves an intensified process where the reaction times are precisely controlled down to a few seconds to minutes. The process presented in the present invention lead to robust process with significant reduction in reactions times due to enhanced kinetics while achieving better quality attributes.
In further embodiments, pharmaceutically acceptable salts of the compounds of the invention include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, ascorbate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Preferably tartrate, tosylate and mesylate. Pharmaceutically acceptable salts of compounds of the invention, may be prepared, respectively, by one or more of three methods: (i) by reacting the compound with the desired acid or base; (ii) by removing an acid- or base-labile protect- ing group from a suitable precursor of the compound of the invention, or by ring- opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of the invention, to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.
DEFINITION
The following definitions are used in connection with the present disclosure unless the context indicates otherwise. “Halogen” is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine. Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxycarbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl, benzyl, p-methoxy benzyl, trityl and the like. Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.
EXAMPLES:
Example 1: Preparation of (S)-2-(4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (IXa):

To a solution of (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (63.8 g) in dimethylacetamide (500 mL) was added with DIPEA (133.0 g) at 0-5 °C. Subsequently, 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Xa) (100 g) was introduced into the reaction mass at the same temperature. Temperature of the reaction mass was raised to room temperature and stirred for 5-6 hrs. Methyl tert-butyl ether (1000 mL) was added into the reaction mass and temperature of the reaction mass was raised to 40-45 °C. DM water (1000 mL) was added to the above reaction mixture and stirred. Layers were separated, organic layer was washed with DM water (1000 mL) and the separated organic layer was distilled off to afford a solid which was co-distilled with n-Heptane (500 mL) at 45-50 °C. Subsequently, Methyl tert-butyl ether (100 mL) and heptane (500 mL) were added to the above reaction mass and stirred at 45-50 °C for 1 h. Reaction mass was cooled to 25-30 °C and stirred for 1-2 h. Solids thus obtained were filtered and washed with n-heptane (500 mL) and dried to get the title compound (IXa) (92.80 g).
Example-2: Preparation of tert-butyl (S)-4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (VIIIa):

To a solution of (S)-2-(4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (IXa) (85.0 g) in acetonitrile (850 mL) was added DIPEA (273 mL) at 0-5 °C. Subsequently, Boc anhydride (97.0 g) was added to the reaction mass at the same temperature. Temperature of the reaction mass was raised to room temperature and stirred for 12-18 h at the same temperature. Dichloromethane (850 mL) and DM water (850 mL) were added into the reaction mass and stirred. Separated aqueous layer was back extracted with dichloromethane (425 mL). Combined organic layer was washed with 10% brine solution (850 mL) and DM water (850 mL). The separated organic layer was dried over sodium sulphate and distilled off to afford a solid, which was then recrystallized in MTBE (85 mL) and heptane (425 mL) to afford the title compound (VIIIa) (92.20 g).
Example 3: Preparation of tert-butyl (S)-4-(7-benzyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine
-1-carboxylate (VIa):

To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (VII) (20.51 g) in THF (215 mL) was added a solution of sodium tert-butoxide (2.0 M in THF, 66.82 mL) slowly in a dropwise manner at 25-30 °C. Separately, a solution of tert-butyl (S)-4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (VIIIa) (43.0 g) in THF (430 mL) was added to the above solution dropwise at 25-30 °C. The reaction mass was maintained at the same temperature for 12-16 h. Ethyl acetate (430 mL) and DM water (430 mL) were charged into the reaction mass and stirred. After layers are separated, organic layer was washed with DM water (430 mL) and the separated organic layer was dried over sodium sulfate and distilled off to afford a residue which was co-distilled with MTBE (2×215 mL). The resultant solid was charged with MTBE (215 mL) and stirred for overnight at room temperature. The reaction mass was filtered and washed with MTBE (2 X 125 mL) and dried under suction to get the title compound (VIa) (37.2 g).
Example 4: Preparation of tert-butyl (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (Va): Method A:

To as solution of tert-butyl-(S)-4-(7-benzyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (VIa) (2.0 g) in methanol (40 mL) was added 10% Pd/C (0.2 gm, 50% wet) at 25-30 °C. The reaction mass was sparged with nitrogen under stirring for 15 min at 25-30 oC. The temperature of the reaction mass was raised to 60-65 °C and hydrogenated at a pressure of 6.0 kg/m2 for 24 h. The reaction mass was filtered over Celite and washed with methanol (5 mL). The resulting filtrate was distilled to obtain the crude residue, which was then purified by using column chromatography to obtain the title compound (1 g). Method B: To as solution of tert-butyl-(S)-4-(7-benzyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (VIa) (12.0 g) in methanol (240 mL) was added 20% Pd(OH)2 (2.2 gm, 50% wet) at 25-30 °C. The reaction mass was sparged with nitrogen under stirring for 15 min at 25-30 oC. The temperature of the reaction mass was raised to 60-65 °C and hydrogenated at a pressure of 6.0 kg/m2 for 24 h. The reaction mass was filtered over Celite and washed with methanol (60 mL). The resulting filtrate was distilled to obtain the crude residue, which was then purified by using column chromatography to obtain the title compound (6.4 g).
Example 5: Preparation of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (IIIa):

To a solution of tert-butyl-(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (Va) (25.0 g) in toluene (250 mL) was added Xantphos (6.13 gm), Cs2CO3 (43.2 gm) and 1,8-Bromochloro naphthalene (12.8 gm) at 25-30 °C. Subsequently, reaction mass was purged with Nitrogen gas for 20 minutes and then added addition of palladium acetate (1.78 g, 0.15 eq.). Temperature of the reaction mass was raised to 85±5 °C and maintained the reaction for 12h at the same temperature. The reaction mass was filtered over Celite bed, washed with Toluene (125 mL). The resulting filtrate was distilled to obtain the crude residue, which was then purified by column chromatography to afford the title compound (IIIa) (9.5 g).
Example 6: Preparation of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(II):

To a solution of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (III) (3.0 g) in acetone (45 mL) was added Conc. hydrochloric acid (0.86 g) at 25-30 °C and stirred at the same temperature for 12 h. The pH of the reaction mass was adjusted to 9-10 by adding a solution of sodium carbonate. Organic layer was separated and aqueous layer was extracted with ethyl acetate. Combined organic layers were dried over sodium sulphate and distilled to afford the title compound (II) (1.9 g).
Example 7: Purification of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (II): A solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (II) (35.0 g) (HPLC Purity- 95.83%) in IPA (105 mL) was heated to 30-35 oC and stirred for 15 min at the same temperature. DM Water (105 mL) was transferred slowly and stirred for 30-60 min. Subsequently, a seed of the above material (200 mg) was transferred into the reaction mass and stirred the reaction mass for 30-60 min at 30-35 oC. Reaction mass was cooled to 25-30 oC and stirred for overnight during which solid precipitation was observed. Subsequently, reaction mass was cooled to 10-15 oC and stirred for 4-5 h. Reaction mass was filtered & dried to afford the title titled compound (27.1 g). HPLC Purity-99.41%
Example 8: Preparation of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (2R,3R)-2,3-dihydroxysuccinate (XIa):

To a solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (II) (0.8 g) in ethyl acetate (12 mL) was slowly added a solution of L-Tartaric acid (1 eq.) in ethyl acetate (4.0 mL) at 45-50 oC. The reaction mixture was stirred for 1 h at the same temperature. Reaction mixture was then cooled to room temperature and stirred at the same temperature for 1 h. Obtained solids was filtered and dried to get the title compound (XIa) (0.9 g). 1H NMR (500 MHz) (DMSO-d6): d 7.91(d, 1H, J = 7.5 Hz), 7.74 (d, 1H, J = 8.0 Hz), 7.58 (dd, 1H, J = 7.5, 1.0 Hz), 7.53 (t, 1H, J = 8.0 Hz), 7.44 (t, 1H, J = 7.5 Hz), 7.33 (d, 1H, J = 8.0 Hz), 4.40-4.29 (m, 2H), 4.20-4.15 (m, 4H), 4.02 (d, 1H, J = 12.0 Hz), 3.88 (t, 1H, J = 7.0 Hz), 3.75-3.69 (m, 1H), 3.49-3.47 (m, 1H), 3.31-3.25 (m, 2H), 3.13-3.04 (m, 2H), 2.99-2.94 (m, 2H), 2.87-2.81 (m, 1H), 2.78 (s, 1H), 2.75-2.68 (m, 3H), 2.66 (d, 3H, J = 3.5 Hz), 2.52-2.50 (m, 1H), 2.08 (s, 3H), 1.95 (s, 1H), 1.87-1.81 (m, 2H), 1.74-1.71 (m, 1H).
Example 9: Preparation of Adagrasib (I): To a solution of 2-Fluoroacrylic acid (0.88 g) in dichloromethane (10 mL) was added trimethylamine (1.66 g) at 0-5 oC and stirred for 10 min at the same temperature. Subsequently, 2,4,6-trichlorobenzyol chloride (2.4 g) and DMAP (0.08 g) were charged into the reaction mass and stirred for 30 min at 0-5 oC. A solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (II) (3.5 g) dissolved in dichloromethane (40) was added to the above reaction mass and stirred at room temperature for 5 h. The reaction mass was quenched with 10% Aq. NaHCO3 solution (35 mL) and extracted with dichloromethane (35 mL). organic layer was washed with 10% Aq NaCl solution (35 mL). The resulting organic layer was distilled to get crude which was purified by column chromatography using 3%MeOH/DCM solution to obtain title compound (I) (0.25 g). NMR: 1H NMR (500 MHz) (DMSO-d6): d 7.90 (d, 1H, J = 10.0 Hz), 7.73 (dd, 1H, J = 11.0, 7.0 Hz), 7.57-7.54 (m, 1H), 7.53-7.49 (m, 1H), 7.43 (t, 1H, J = 10.0 Hz), 7.32 (dd, 1H, J = 20.0, 10.0 Hz), 5.75 (s, 1H), 5.39 (dd, 1H, J = 20.0, 5.0 Hz), 5.27 (bd, 1H), 4.92-4.64 (broad peak,1H), 4.26 (ddd, 1H, J = 15.0, 10.0, 5.0 Hz), 4.21-4.15 (m, 1H), 4.11-3.97 (m, 3H), 3.89 (bd, 1H), 3.79-3.71 (m, 1H), 3.50-3.35 (m, 4H), 3.25-3.22 (dd, 1H, J = 15.0, 5.0 Hz), 3.17-3.02 (m, 3H), 2.99-2.91 (m, 2H), 2.70-2.67 (bd, 1H), 2.60 (bs, 1H), 2.35 (d, 3H, J = 5.0 Hz ), 2.24-2.19 (m, 1H), 1.98-1.89 (m, 1H), 1.70-1.64 (m, 2H), 1.62-1.56 (m, 1H). Mass: 604.44 (M+H+).
Example 10: Dibenzoyl-L-tartaric acid salt of adagrasib (XIIa). To a solution of Adagrasib (I) (2.8 g, 85.53% purity by HPLC) in Isopropyl acetate [IPAc] (42 mL) was added 20% W/W charcoal (SC-40) 45-50 oC and stirred for 1 h at the same temperature. The reaction mixture was then filtered at the same temperature through celite and washed with IPAc (14 mL). The resulting filtrate was distilled and obtained residue was mixed with IPAc (28 mL). The temperature of the reaction mass was allowed to raise to 45-50 oC. Dibenzoyl-L-tartaric acid (0.84 g) dissolved in (14 mL of IPAc) was added to the above reaction mass slowly, stirred for 1 h at 45-50 oC and subsequently cooled down to room temperature and stirred at RT for 1 h. The resulting mass was filtered and dried to get the title compound, which was further mixed with MTBE (42 mL) and heated to 45-50 oC, maintained for 1h. The reaction mass was cooled down to room temperature and stirred at RT for 1 h and filtered. The resulting solid was dried to get the title compound (XIIa) (2.5 g). XRD of dibenzoyl tartrate salt of Adagrasib was found to be amorphous in nature. NMR Data: 1H NMR (500 MHz) (DMSO-d6): d 7.96-7. 7.912 (m, 4H), 7.76-7.74 (m, 1H), 7.65-7.43 (m, 9H), 7.37-7.32 (dd, 1H, J = 15.0, 7.5 Hz), 5.75-5.70 (m, 2H), 5.40-5.22 (m, 2H), 4.45 (bs, 2H), 4.19-3.92 (m, 4H), 3.76 (t, 2H, J = 17.5 Hz), 3.49-3.43 (m, 3H), 3.26-3.31 (m, 2H), 3.11-3.07 (m, 7H), 3.00-2.90 (m, 2H), 2.77-2.69 (m, 3H), 2.12-2.10 (m, 1H), 1.85-1.80 (m, 2H), 1.72-1.71 (m, 1H).
Example 11: Preparation of Adagrasib API via the dissociation of Dibenzoyl tartrate salt of Adagrasib (I): To a solution of Dibenzoyl tartrate salt of Adagrasib (XIIa) (1.0 g) in DCM (10 mL) was added an aqueous sodium carbonate solution (10 mL, 10 % solution). The resultant reaction mass was stirred at 25-30 ? C for 1h. Layers were separated. Organic layer was distilled under vacuum to obtain Adagrasib (I) 0.7 g. XRD of Adagrasib was found to be Amorphous in nature.
Example 12: Purification of Adagrasib (I): Crude Adagrasib (I) (2 g) was dissolved in t-butanol (10 mL) and the mixture was heated to 55-65 oC and stirred for 30 min at the same temperature. Water (2 mL) was slowly added to the reaction mixture and stirred for 30 min. Reaction mass was cooled to 25-30 oC and stirred for overnight during which solid precipitation was observed. Reaction mass was filtered & dried to afford Adagrasib (1.3 g) with purity 99.54% by HPLC.
Example 13: Preparation of p-TSA salt of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate
Method A: To a solution of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)
piperazine-1-carboxylate (IIIa) (10 g) in toluene (170 mL) was added p-TSA.H2O (3.38 g) and acetone (10 mL) at room temperature. The reaction mixture was stirred for 6 hours at the same temperature. The reaction mixture was cooled to 0 oC and stirred for 3 hours. The resulting solid was then filtered and washed with toluene (50 mL), dried under vacuum at 50 oC for 5 hours to obtain the title compound (13 g).
Method B: A solution of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)
piperazine-1-carboxylate (IIIa) (5.6 g) in toluene was distilled under vacuum and the resulting crude was co-distilled with IPA (56 mL) and MTBE (56 mL) . The distilled crude was dissolved in IPA (22 mL) under stirring at room temperature. p-TSA.H2O (1.65 g) was added to the above solution. The reaction mixture was heated to 50 oC. MTBE (90 mL) was slowly added to the reaction mixture at the same temperature. The reaction mixture is then cooled to room temperature and allowed for 30 minutes at the same temperature. The resulting solid was filtered and washed with MTBE (33 mL), vacuum dried. The wet solid was further dried in VTD at 50 oC for 4 hours to obtain the title compound (5.93 g).
Method C: A solution of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-cyanomethyl)
piperazine-1-carboxylate (IIIa) (5 g) in toluene was distilled under vacuum and the resulting crude was co-distilled with acetone (2 X 50 mL) followed by MTBE (50 mL). The distilled crude was dissolved in acetone (35 mL) under stirring at room temperature. p-TSA.H2O (1.69 g) was added to the above solution. The reaction mixture was heated to 40 oC under stirring. MTBE (50 mL) was slowly added to the reaction mixture at the same temperature. The reaction mixture is then cooled to room temperature and allowed for 2 hours at the same temperature. The resulting solid was filtered and washed with MTBE (15 mL), vacuum dried. The wet solid was further dried in VTD at 50 oC for 30 minutes to obtain the title compound (4.6 g).
Example 14: Preparation of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (II): To a solution of p-TSA slat of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (4.0 g) in IPA (20 mL) was added IPA.HCl (16 mL) at 25-30 °C and stirred at the same temperature for 24 h. The reaction mixture was filtered and washed with IPA (8 mL). The wet solid was further dried under vacuum at 50 oC for 12 hours to obtain the title compound (2.85 g).
Example 15: Preparation of Adagrasib using flow reactor:
Feed preparation: Pump 1: 2.5eq 2-fluoroacrylic acid (4.23 g) in DMF (50 mL) at RT; Pump 2: Triethylamine (14.26 g) dissolved in DMF (20 mL) at RT; Pump 3: T3P (18.63 g) dissolved in DMF (25 mL) at RT; Pump 4: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (II) (10 g) dissolved in DMF (70 mL) at RT.
2-fluoroacrylic acid (2-FAA) pump and triethylamine (TEA) pumps started initially and given 3 times RT1(1.87 min) for first reaction stabilization at 60-65 oC. T3P pump was then started and given 3 times RT2(2.28 min) for second reaction stabilization 60-65 oC. 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (II) pump was then started and given 3 times RT3 (1.5 min) for 3rd reaction stabilization 60-65 oC. Post stabilization of 3rd reaction product has been collected for UPLC/HPLC. The reaction mass was quenched with Na2CO3 to obtain the title compound (purity by HPLC: 98.64%).

Dated: 20th Day of March 2025.
Signature: _________________
Dr. B. Dinesh Kumar.
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited.
ABSTRACT

,CLAIMS:We Claim:
1. Process for the preparation of Adagrasib (I) or its pharmaceutically acceptable salts thereof, comprising reacting compound of formula (II) with 2-fluoroacrylic anhydride or mixed anhydride of 2-fluoroacrylic acid to produce compound of formula (I) or its pharmaceutically acceptable salts thereof,
.

2. Mixed anhydrate as claimed in claim 1), prepared by reacting 2-fluoroacrylic acid with a second suitable acid or acid derivative in presence of a suitable base.

3. Second suitable acid or acid derivative as claimed in claim 2) includes but not limited to carboxylic acids or their derivatives such as pivalic acid or pivaloyl chloride; benzoic acid or their derivatives such as 2,4,6-trichlorobenzoic acid, 2,4,6-trichlorobenzoyl chloride; carbonic acid derivatives such as ethyl chloroformate and isobutyl chloroformate, Boc anhydride; boric acid; and sulfonic acids or their derivatives such as p-toluenesulfonic acid or p-toluenesulfonyl chloride and methanesulfonic acid or methanesulfonyl chloride; preferably, the second suitable acid or acid derivative is 2,4,6-trichlorobenzoic acid, 2,4,6-trichlorobenzoyl chloride (2,4,6-tribromobenzoyl chloride).

4. Process for preparation of compound of formula (VI) or its pharmaceutically acceptable salts thereof, comprising reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base to produce compound of formula (VI) or its pharmaceutically acceptable salts thereof,
.
wherein X is a halogen; P1 and P2 are same or different amino protecting groups.

5. Process for preparation of Adagrasib (I) comprising the following steps:
a) reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable base to produce compound of formula (VI) or its pharmaceutically acceptable salts thereof,
;
b) deprotecting compound of formula (VI) in presence of a suitable reagent to provide compound of formula (V);
;
c) reacting compound of formula (V) with compound of formula (IV) to provide compound of formula (III) or salt thereof
;
d) deprotecting compound of formula (III) to compound of formula (II) or salt thereof in presence of a suitable reagent
;
e) reacting compound of formula (II) with 2-fluoroacrylic anhydride or mixed anhydride of 2-fluoroacrylic acid to produce compound of formula (I) or its pharmaceutically acceptable salts thereof,
;
Wherein P1 and P2 are same or different amino protecting groups.

6. Compound of formula (XII) and/or (XIIa) and/or (XI) and/or (XIa).
.