DESC: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 and has following structural formula:

(I)
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)
;
d) deprotecting compound of formula (III) to compound of formula (II) in presence of a suitable reagent
;
e) reacting compound of formula (II) with an 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.

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; 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 pivalic acid or pivaloyl 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. Specifically, suitable base is selected from organic base. More specifically, base is triethylamine (TEA). 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, 2-MeTHF. 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.
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.
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, 2-MeTHF. 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, isopropanol (IPA). 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 tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3]. 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 or BINAP. 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 c), isolation of compound of formula (III) 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 p-toluenesulfonic acid.
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 and the like. Specifically, the suitable reagent may be hydrochloric 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) is 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 include 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. More specifically, acetonitrile. 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. 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 e) 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) is 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; carbonic acid derivatives such as ethyl chloroformate and isobutyl chloroformate; 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 pivalic acid or pivaloyl 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. Specifically, suitable base is selected from organic base. More specifically, base is triethylamine (TEA). Suitable solvent includes 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 of step e) 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 another embodiment, the present application relates to an acid addition salt of compound of formula (Va). Preferably tartrate salt of compound of formula (Va).
.
In another embodiment, the present application relates to an acid addition salt of compound of formula (IIIa). Preferably tosylate salt of compound of formula (IIIa).

A specific aspect of the present application relates to a process for preparation of compound of formula (II) comprising the deprotection of the compound of formula (IIIa) using a suitable reagent
;
In a further embodiment, the inventors of the present application surprisingly found that conversion of compound of formula (IIIa) to compound of formula (II) in concentrated hydrochloric acid/acetone condition provided better yield and purity compared to other processes/conditions. Details are given below:
S. No. Condition Purity (% by HPLC) of the crude material Purity (% by HPLC) after purification Observation
1 TFA, DCM 86 98 No precipitation of the product as a salt was observed.
Product was isolated by extraction after basification of reaction mixture.
2 PTSA.H2O, DCM 88 ---
3 HCl in Dioxane 55 88
4 Concentrated hydrochloric acid, DCM 52 89
5 Concentrated hydrochloric acid, Acetone 90 99 The product precipitated out as an HCl salt which was filtered and basified to isolate the free base.
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 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 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.
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 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) (5.98 g) in 2-methyl-THF (125 mL) was added sodium tert-butoxide (3.73 g) at 0-5 °C under argon atmosphere. The reaction mixture was warmed to room temperature and stirred at the same temperature for 30-45 minutes. 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) (12.5 g) was added to the above reaction mixture at room temperature, which was then heated to 70-75 °C and stirred at the same temperature for 8 h. The reaction mixture was cooled to 0 °C. Water (62.5 mL) was added to the above reaction mixture and stirred at 0 °C for 10-15 min. The organic layer was separated and aqueous layer which was extracted with 2-methyl-THF (3 X 50.0 mL). The combined organic layers were washed successively with water (187.5 mL) and brine (62.5 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure at 45 °C. The obtained crude product was purified by column chromatography using silica gel (MeOH/DCM: 6:94) to obtain the title compound a pale yellowish brown solid (VIa) (12.06 g).
Example 2: 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): To a 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) (100 g) in 2-propanol (IPA) (3.0 L) was added 10% Pd-C (50.0 g) at 25-30 °C and the reaction mass was sparged with nitrogen under stirring for 15 min at 25-30 oC. The nitrogen was replaced with hydrogen and the reaction mixture was sparged for 5 min at 25-30 oC. The reaction mixture was stirred at 60 oC for 28-29 h under 20 psi hydrogen pressure. The reaction mixture was cooled to 25-30 oC and filtered through celite and washed with IPA (2?500 mL). The combined filtrates were concentrated under reduced pressure. The obtained semi solid was dissolved in 2-MeTHF (350 mL) at 25-30 oC and the solution was heated to 55 oC under nitrogen atmosphere. To this vigorously stirred solution was added a solution of L-tartaric acid (26.71 g) in IPA (450 mL) at 55 oC over a period of 30 min and the reaction mixture was further stirred overnight at 25-30 oC under nitrogen atmosphere. The resulting suspension was diluted with 2-MeTHF (1.0 L), stirred for 30 min and filtered under nitrogen atmosphere at 25-30 oC. The filter cake was washed with 2-MeTHF (2?500 mL) and dried under nitrogen atmosphere at 25-30 oC. The obtained off-white solid was dissolved in water (1.0 L). The solution was washed with dichloromethane (2?1.0 L), basified to pH 8-9 with solid NaHCO3 and then extracted with dichloromethane (2?1.5 L). The combined dichloromethane extracts were successively washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and finally concentrated under reduced pressure below 50 oC to obtain the title compound (Va) as an off-white solid (57.0 g).
Example 3: 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) (57.0 g) in anhydrous toluene (855.0 mL) was added 1-bromo-8-chloronaphthalene (IV) (58.34 g), Cs2CO3 (78.718 g) and Xantphos (13.979 g) at 25-30 °C under nitrogen atmosphere. The reaction mixture was sparged with nitrogen for 70 min at 25-30 °C. Pd2(dba)3 (11.06 g) was added in to the above reaction mixture which was sparged further for 15-20 min with nitrogen and then was heated at 95-100 oC for 16-18 h. The reaction mixture was cooled to room temperature and filtered through Celite. The celite bed was washed with toluene (2?285 mL). The combined filtrates were concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (570 mL) and washed with water (570 mL) and brine (285 mL), dried over anhydrous Na2SO4 and filtered. The Na2SO4 bed was washed with DCM (2?285 mL). The filtrate and washings were combined and concentrated under reduced pressure at 49 oC to obtain the title compound (IIIa) (142.0 g, crude). The crude product was proceeded to the next step without further purification.
Example 4: 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 (IIIa) (crude, 9.78 g) in acetone (73.0 mL) was added Conc. HCl (3.39 g, 9.68 mL of 35% aq. solution) at 25-30 °C under nitrogen atmosphere. The reaction mixture was stirred for 2-3 h under nitrogen atmosphere at 25-30 °C. The reaction mixture was then diluted with acetone (110.0 mL) and stirred at 25-30 °C for 30 min. The resulting suspension was filtered and obtained solid was washed with acetone (2 X 36.5 mL), dried under nitrogen for 45 min at 25-30 °C. The resulting solid was dissolved in water (73.0 mL). 2-Methyl-THF (73.0 mL) was added to the obtained aqueous solution which was then basified (pH = 8-9) at 25-30 °C under vigorous stirring with 10% aqueous sodium bicarbonate solution (51.0 mL). The organic layer was separated and aqueous layer was then extracted with 2-methyl-THF (2 X 110 mL). The combined organic layers were washed with brine (36.5 mL), dried over anhydrous Sodium sulfate and concentrated under reduced pressure at 45 °C. The resulting crude product was purified by column chromatography using silica gel [methanolic ammonia/EtOAc-hexanes (1:1) = 5:95] to obtain the title compound as a pale brown solid (II) (yield: 4.52 g).
Example 5: Preparation of Adagrasib (I): 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) (0.154 g) in dry acetonitrile (1.54 mL) was added 2-fluoroacrylic anhydride (0.07 g ) at 30-35 °C under nitrogen atmosphere. The reaction mixture was stirred for 10-20 minutes at the same temperature. The reaction mixture was treated with aqueous TFA solution (1.54 mL, 0.25%) at 30-35 °C, followed by water (1.54 mL), and then extracted with ethyl acetate (3?4.62 mL). The ethyl acetate extracts were washed with brine (1.54 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using silica gel (methanolic ammonia and dichloromethane, 2:98) to obtain the title compound (I) (0.135 g).
Example 6: Preparation of Adagrasib (I): To a solution of 2-fluoroacrylic acid (50 mg, 0.0005 mole) in dry dichloromethane (1.5 mL) was added triethylamine (0.19 mL) in a dropwise manner at room temperature under nitrogen atmosphere. The reaction mixture was cooled to 0-5 °C. Pivaloyl chloride (0.075 mL) was slowly added to the above reaction mixture at 0-5 °C. The resulting suspension brought to room temperature and stirred for 2-3 h. 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) (0.147 g) in dry DCM (1 mL) was added to the above reaction mixture at room temperature and stirred for 2-3 h at the same temperature. A second lot of the mixed anhydride was prepared separately by adding pivaloyl chloride (0.075 mL) into a mixture of 2-fluoro acrylic acid (50 mg), dry DCM (1.5 mL) and distilled TEA (0.19 mL) maintained at 0-5 °C under nitrogen atmosphere. The brown suspension obtained was stirred at RT for 1-2 h and then added into the amidation reaction mixture which was then stirred at RT for 1-2 h. Water (10 mL) followed by dichloromethane (50 mL) were added to the above reaction mixture and stirred for 10 min at room temperature. The organic layer was separated and aqueous layer which was extracted with DCM (2?20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and finally concentrated under reduced pressure at 35 °C. The resulting crude product was purified by column chromatography using silica gel (2% methanolic ammonia and DCM) to obtain the title compound as pale yellow solid (I) (0.020 g).
Example 7: Telescopic process for 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)-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) (100 g) in methanol (1.5 L) was added 10% Pd-C (10.4 g) followed by ammonium formate (28.1 g) at 25-30 °C. The reaction mixture was heated to 60 oC and stirred for 3 hours at the same temperature. The reaction mixture was cooled to 25-30 oC and filtered through hyflow and washed with methanol (2?200 mL). The combined filtrates were concentrated under reduced pressure at below 50 oC. The obtained solid was co-distilled with acetone (2 X 5V) to obtain the title compound (Va) as crude solid (80.3 g), which was proceeded to the next step without further purification.
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) (30.0 g) in anhydrous toluene (300.0 mL) was added 1-bromo-8-chloronaphthalene (IV) (15.36 g), Cs2CO3 (83 g) and R-BINAP (3.17 g) at 25-30 °C under nitrogen atmosphere. The reaction mixture was sparged with nitrogen for 20 min at 25-30 °C. Pd2(dba)3 (2.33 g) was added in to the above reaction mixture under nitrogen atmosphere. The reaction mixture was heated at 90 °C and stirred for 24 h at the same temperature. The reaction mixture was slowly cooled to room temperature and treated with Activated Carbon 10% PF Ultra for about 15 minutes. The reaction mixture was filtered through hyflow and washed with toluene. The resulting filtrate was divided in to 3 equal parts. One part of the resulting filtrate was evaporated under reduced pressure and then co-distilled with acetone (50 mL) at room temperature. The resulting solid was mixed with MTBE (10 mL) and stirred for 12h at the same temperature. The reaction mixture was cooled to 0 °C and maintained at the same temperature for 1 h. The resulting solid was filtered and washed with MTBE (50 mL), dried in VTD at 35 °C for about 6 h to get the title compound [8.2 g].
Example 8: Telescopic process for 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): Second part of resulting filtrate of example 7 (compound of formula IIIa, 10 g) was mixed with water (100 mL) and reaction mixture was cooled to 0 °C. Aqueous hydrochloric acid (100 mL) was slowly added to the above reaction mixture and stirred for 30 minutes at the same temperature. Reaction mixture was slowly heated to room temperature and stirred at the same temperature for 2 h. Layers were separated and aqueous layer was washed with IPAc (2 X 100). Aqueous layer was separated and cooled to 10 °C. Saturated solution of sodium bicarbonate (40%, 100m L) solution was slowly added to the above aqueous solution. Reaction mixture was brought to room temperature and layers were separated. Aqueous layer was extracted with IPAC (3 X 50 mL). Layers were separated and aqueous layer was extracted with ethyl acetate (3 X 50 mL). Combined organic layers were washed with water. Organic layer was treated with ultra Carbon and filtered through hyflow, washed with IPAc (20 mL). Filtrate was distilled under vacuum and the resulting residue was dissolved in DMAc (40 mL). Water (10 mL) was slowly added to the above solution and cooled to 15 °C. Seed material was slowly added to the reaction mixture. Water (25 mL) was slowly added to the reaction mixture. Solid separation observed. Resulting solid was filtered and washed with mixture of water and DMAc, dried under vacuum. Resulting solid was dissolved in IPA (30 mL). water was slowly added to the above solution. A seed material was added to the above reaction mixture and reaction mixture was maintained for 2 h at room temperature. Finally resulting solid was filtered, washed with water (10 mL) and dried under vacuum to get the title compound (7.5 g).
Example 9: Telescopic process for 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 (IIIa): Third part of resulting filtrate of example 7 (compound of formula IIIa, 10 g) was treated with 10% charcoal (0.5 g) and stirred the reaction mixture for 30 minutes. The reaction mixture was then filtered and distilled under vacuum. The resulting residue was taken in a mixture of acetone (20 mL) and MTBE (100 mL). p-TSA (1.50 g) was added to the above reaction mixture and stirred for 12 h at room temperature. The resulting solid was filtered and washed with MTBE (100 mL) to obtain the title compound.

Dated: 8th Day of November 2024.
Signature: _________________
Dr. B. Dinesh Kumar.
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited.
,CLAIMS:
CLAIMS:
1. 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,
.
2. The process as claimed in claim 1) where in suitable base is selected from group of organic base such as triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine, etc.
3. 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.
4. The process as claimed in claim 3) wherein suitable base is a metal alkoxide base such as sodium methoxide, sodium t-butoxide, etc.
5. 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) to compound of formula (II) in presence of a suitable reagent
;
e) reacting compound of formula (II) with an 2-fluoroacrylic anhydride or mixed anhydride of 2-fluoroacrylic acid to produce compound of formula (I) or its pharmaceutically acceptable salts thereof,
;
Wherein X is a halogen; P1 and P2 are same or different amino protecting groups.

6. 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,
.

7. An acid addition salt of compound of formula (Va) and (IIIa)