DESC:Field of the invention:
The present invention relates to a novel process for the preparation of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one compound of formula-1 which is represented by the following structural formula:

Formula-1

The present invention also relates to novel intermediate compounds of formula-1 as well as its process for the preparation.

Background of the Invention:
The drug substance 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl] pyrido[2,3-d]pyrimidin-2(1H)-one is commonly known as “Sotorasib”.
Sotorasib has been approved by U.S. Food and Drug Administration (FDA) in May, 2021 which is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib is marketed by Amgen Inc under the brand name Lumakras and Lumykras.

US10519146B2 disclosed a process for the preparation of Sotorasib which is illustrated in below Scheme-I:

The process disclosed in US10519146B2 involves the usage of corrosive chemicals and also involves the column purification techniques for the isolation of Sotorasib which is not suitable for the commercial scale production.
Moreover, the process required SFC (chiralpack column) to separate the desired (M)-atropisomer of Sotorasib from Sotorasib. The Separation of the compound by chiral column may drastically decrease the yield of the desired compound which is not viable for commercial scale process.
In view of the above, there remains a need to develop a cost effective and commercially viable process for the preparation of (M)-atropisomer of Sotorasib.

Brief description of the Invention:
The first aspect of the present invention is to provide a novel process for the preparation of Sotorasib compound of formula-1.
The second aspect of the present invention is to provide novel intermediate compounds of Sotorasib and its process for the preparation.

Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N, N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane/methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert.amyl alcohol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.
As used herein the present invention the term “suitable acid” refers to organic acids or inorganic acids. The “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like or mixtures thereof.
As used herein the present invention the term “suitable base” refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention is to provide a novel process for the preparation of Sotorasib compound of formula-1, comprising of:
a) Reacting the 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione of formula-2,

Formula-2
with 2-(2-fluoro-6-methoxyphenyl)-4,4,5.5-tetramethyl-1,3,2-dioxaborolane of formula-3

Formula-3
in presence of a suitable base and catalyst in a suitable solvent to provide 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione of formula-4,

Formula-4
b) treating the compound of formula-4 in-situ with phosphorus oxychloride in presence of a suitable base in a suitable solvent to provide 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido [2,3-d]pyrimidine-2-one of formula-5,

Formula-5
c) reacting the compound of formula-5 in-situ with (3S)-3-methyl-1-piperazinecarboxylic acid 1,1-dimethylethyl ester of formula-6,

Formula-6
in presence of a suitable base in a suitable solvent to provide tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, optionally purifying the compound from a suitable solvent to provide pure compound of formula-7,

Formula-7
d) deprotecting and demethylating the compound of formula-7 using a suitable Lewis acid in a suitable solvent to provide 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, optionally purifying the compound from a suitable solvent to provide pure compound of formula-8,

Formula-8
e) treating the compound of formula-8 with acryloyl chloride in presence of an acid in a suitable solvent to provide compound of formula-1, optionally purifying the compound from a suitable solvent to provide pure compound of formula-1.

In step (a) of the present invention, the catalyst used in the condensation of compound of formula-2 with compound of formula-3 is Pd(dppf)Cl2. MDC complex or any other palladium derived catalyst.
The base used in step-a), b) & c) is an organic or inorganic base. The organic base is selected from N,N-diisopropylamine, N,N-diisopropylethylamine, triethylamine, N,N-dimethylamine, trimethylamine, pyridine; the inorganic base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof.
In step (d) & (e) of the present invention, the acid used is selected from organic or inorganic acid. The organic acid may be selected from methanesulfonic acid, trifluoroacetic acid, triflic acid, p-toluenesulfonic acid, cyanuric acid or any other suitable organic acid. The inorganic acid may be selected from dilute or concentrated acids, hydrochloric acid, ortho phosphoric acid, hydrobromic acid, HBr in acetic acid, boron tribromide (BBr3) or any other suitable inorganic acid.
In step-a, b, c, d & e) the suitable solvent is selected from alcoholic solvents, polar-aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

In a preferred embodiment of the present invention is to provide a novel process for the preparation of Sotorasib compound of formula-1, comprising of:
a) Reacting the 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione of formula-2 with 2-(2-fluoro-6-methoxyphenyl)-4,4,5.5-tetramethyl-1,3,2-dioxaborolane of formula-3 in presence of aqueous potassium carbonate and Pd(dppf)Cl2.MDC complex in 1,4-dioxane provides 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione of formula-4,
b) treating the compound of formula-4 in-situ with phosphorus oxychloride in presence of diisopropylethylamine in toluene provides 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido [2,3-d]pyrimidine-2-one of formula-5,
c) reacting the compound of formula-5 in-situ with (3S)-3-methyl-1-piperazinecarboxylic acid 1,1-dimethylethyl ester of formula-6 in presence of diisopropylethylamine in isopropyl acetate provides tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, purifying the compound using isopropyl acetate provides pure compound of formula-7,
d) deprotecting and demethylating the compound of formula-7 using boron tribromide (BBr3) and trifluoroacetic acid in dichloromethane provides 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, purifying the compound using aqueous ethanol provides pure compound of formula-8,
e) treating the compound of formula-8 with acryloyl chloride in presence of trifluoroacetic acid in N-methyl-2-pyrrolidone provides compound of formula-1, purifying the compound using aqueous ethanol and trifluoroacetic acid followed by acetonitrile provides pure compound of formula-1.

The second aspect of the present invention is to provide novel intermediate compounds of Sotorasib and its process for the preparation.
In a preferred embodiment of the present invention provides novel intermediate compounds of Sotorasib which are represented as below:

Formula-4 Formula-5

Formula-7

In a preferred embodiment of the present invention provides a process for the preparation of tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, comprising of:
a) Reacting the 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione of formula-2 with 2-(2-fluoro-6-methoxyphenyl)-4,4,5.5-tetramethyl-1,3,2-dioxaborolane of formula-3 in presence of aqueous potassium carbonate and Pd(dppf)Cl2. MDC complex in 1,4-dioxane provides 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione of formula-4,
b) treating the compound of formula-4 in-situ with phosphorus oxychloride in presence of diisopropylethylamine in toluene provides 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido [2,3-d]pyrimidine-2-one of formula-5,
c) reacting the compound of formula-5 in-situ with (3S)-3-methyl-1-piperazinecarboxylic acid 1,1-dimethylethyl ester of formula-6 in presence of diisopropylethylamine in isopropyl acetate provides tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, purifying the compound using isopropyl acetate provides pure compound of formula-7.

In a preferred embodiment of the present invention provides a process for the preparation of Sotorasib compound of formula-1, comprising of:
a) Deprotecting and demethylating the compound of formula-7 using boron tribromide (BBr3) and trifluoroacetic acid in dichloromethane provides 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, purifying the compound using aqueous ethanol provides pure compound of formula-8,
b) treating the compound of formula-8 with acryloyl chloride in presence of trifluoroacetic acid in N-methyl-2-pyrrolidone provides compound of formula-1, purifying the compound using aqueous ethanol and trifluoroacetic acid followed by acetonitrile provides pure compound of formula-1.

In another preferred embodiment of the present invention provides a process for the preparation of Sotorasib compound of formula-1, comprising of:
a) Deprotecting and demethylating the compound of formula-7 using boron tribromide (BBr3) and trifluoroacetic acid in dichloromethane provides 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, purifying the compound using aqueous ethanol provides pure compound of formula-8,
b) treating the compound of formula-8 with acrylic anhydride of formula-9 in chloroform provides compound of formula-1, purifying the compound using aqueous ethanol followed by acetonitrile provides pure compound of formula-1.

The starting materials of the present invention i.e., compound of formula-2, formula-3 and compound of formula-6 can be prepared from the processes known in the art.

The novel process for the preparation of Sotorasib compound of formula-1 is schematically represented as below:

Scheme-II:

Scheme-III:

An alternate process for the preparation of Sotorasib (Formula-1) from compound of Formula-8 is schematically represented as below:

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples provide as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:

Exampe-1: Process for the preparation of tert-Butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]
pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (Formula-7)
A mixture of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Formula-2, 150 g), 2-(2-fluoro-6-methoxyphenyl)-4,4,5.5-tetramethyl-1,3,2-dioxaborolane (Formula-3, 162.63 g) and degassed 1,4-dioxane (2.25 L) was stirred for 10 min at 25-30 °C to get a clear solution. Potassium carbonate (59.44 g) was dissolved in degassed DM water (300 mL) and charged into the above reaction mass and degassed with nitrogen for 45 min. Pd(dppf)Cl2. MDC complex (21.07 g) was added to the reaction mass and degassed with nitrogen for 45 min at 25-30 °C. Thereafter, the reaction mass was heated to reflux temperature and maintained for 3.5 hours. After completion of reaction (Formula-2 content by HPLC: NMT 0.5%), reaction mass was cooled and solvent was concentrated under reduced pressure at = 60 °C. DM water (450 mL) was added to the gummy mass, 1.0 volume of water was concentrated at = 60 °C and cooled to 25-30 °C. To this, aqueous hydrochloric acid solution (199.5 mL of Conc. HCl diluted with 1.95 L of DM water) was added, stirred for 1 hour at 25-30 °C, filtered and washed with DM water (150 mL). Thereafter, filtrate pH was adjusted to 7-8 with aqueous sodium hydroxide solution (75 g of Sodium hydroxide dissolved in 150 mL of pre-cooled DM water) and stirred for 30 min at 25-30 °C. Product was extracted with toluene (1 L) and treated with aqueous N-acetyl-L-cysteine solution (8.42 g of N-acetyl-L-cysteine dissolved in 150 mL of DM water) for 3 hours at 25-30 °C, filtered and washed with toluene (75 mL). Both layers were separated and organic layer was washed with DM water (2x450 mL) and dried over anhydrous sodium sulphate (30 g) to get 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione (Formula-4).
To a solution of phosphorous oxychloride (85.73 g) in toluene (450 ml) was added diisopropylethylamine (94.5 g) at below 40 °C. Reaction mass heated and above Formula-4 solution was added to the reaction mass over a period of 3.5 hours at 35-40 °C and stirred for 45 min. After completion of reaction (Formula-4 content by HPLC: NMT 1.0%), cooled to 15-20 °C and diluted with dichloromethane (150 mL) to get
4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2-one (Formula-5). Thereafter, (3S)-3-methyl-1-piperazinecarboxylic acid 1,1-dimethylethyl ester (Formula-6, 86.14 g), Isopropyl acetate (225 mL) and diisopropylethylamine (55.59 g) solution was added to the reaction mass and stirred for 1.5 hours at 15-20 °C. After completion of reaction (Formula-5 content by HPLC: NMT 0.5%), quenched the reaction mass with aqueous sodium bicarbonate solution (130 g of sodium bicarbonate dissolved in 2.25 L of DM water) at = 30 °C and stirred for 2.5 hours. Both layers were separated and the aqueous layer was extracted with dichloromethane (150 mL). Combined organic layer was washed with DM water (300 mL) followed by 5% aqueous acetic acid solution (2x300 mL) and DM water (300 mL). Solvent was concentrated under reduced pressure at
= 60 °C and co-distilled with Isopropyl acetate (150 mL). Thereafter, mass was cooled to 25-30 °C, added Isopropyl acetate (450 mL) and stirred for 1 hour. The product was filtered, washed with Isopropyl acetate (225 mL) and suction dried for 30 min.
A mixture of the above wet product and Isopropyl acetate (450 mL) was heated and stirred for 2 hours at 60-65 °C. Further, the reaction mass was cooled to 25-30 °C, stirred for 1 hour, filtered, washed with Isopropyl acetate (225 mL) and dried under vacuum for 4 hours at 65-70 °C to get Formula-7 as an off-white to yellow colored powder (202.5 g).
Purity: 99.5%; Chiral purity: 99.97%.
1H NMR (CDCl3, 400 MHz): d 8.45-8.47 (d, J = 5.2 Hz, 1H), 7.78-7.80 (d, J = 8.4 Hz, 1H), 7.30-7.36 (m, 1H), 7.05-7.06 (d, J = 3.6 Hz, 1H), 6.68-6.73 (m, 2H), 4.84 (br, 1H), 3.98-4.40 (br, 3H), 3.68 (br, 1H), 3.68 (s, 3H), 3.29 (br, 2H), 2.76-2.83 (m, 1H), 1.99 (s, 3H), 1.51 (br, 3H), 1.51 (s, 9H), 1.23-1.24 (d, J = 6.4 Hz, 3H), 1.03-1.05 (d, J = 6.0 Hz, 3H).

Exampe-2: Process for the preparation of 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl] pyrido[2,3-d]pyrimidin-2(1H)-one (Formula-8)
To a solution of Formula-7 (90 g) in dichloromethane (900 mL) was added aqueous N-Acetyl-L-Cysteine solution (10.8 g of N-Acetyl-L-Cysteine dissolved in 180 mL of DM water) and stirred for 3 hours at 25-30 °C. Both layers were separated and organic layer was washed with DM water (90 mL), dried over anhydrous sodium sulphate (9 g) and washed with dichloromethane (90 mL). Trifluoroacetic acid (49.6 g) was added to the organic layer at 0-5 °C and stirred for 1 hour. Thereafter, BBr3 solution (1.0M in MDC, 1305 mL) was added to the reaction mass and stirred for 1 hour at 0-5 °C under nitrogen purging. Reaction mass temperature was raised to 25-30 °C and stirred for 2.5 hours. After completion of reaction (Formula-7 content by HPLC: NMT 1.0%), reaction mass was cooled to 0-5 °C and added to pre-cooled DM water (1350 mL) at 0-5 °C. Reaction mass pH was adjusted to 6-7 with aqueous potassium carbonate solution (337.7 g of potassium carbonate dissolved in 1125 mL of DM water) and stirred for 30 min at 0-5 °C. Thereafter, reaction mass temperature was raised to 25-30 °C and solvent was concentrated under reduced pressure at = 55 °C. Ethyl acetate (450 mL) was added to the mass, stirred for 1 hour, filtered the product at 50-55 °C, washed with ethyl acetate (225 mL) and suction dried for 30 min.
A mixture of above wet product and ethanol (540 mL) was heated to reflux temperature. To this, DM water (90 mL) was added and stirred for 1.5 hour. Thereafter, reaction mass was cooled to 25-30 °C, stirred for 1.5 hours, filtered the product, washed with ethanol (135 mL) and DM water (45 mL) solvent mixture and dried under vacuum for 5 hours at 70-75 °C to get Formula-8 as an off-white to cream colored powder (48.4 g).
Purity: 99.3%; Chiral purity: 100%.
1H NMR (DMSO-d6, 400 MHz): d 10.15 (br, s, 2H), 8.36-8.38 (d, J = 4.8 Hz, 1H), 8.17-8.20 (d, J = 9.2 Hz, 1H), 7.23-7.29 (q, J = 8.4 Hz, 1H), 7.16-7.17 (d, J = 4.8 Hz, 1H), 6.65-6.73 (m, 2H), 4.74 (br, m, 1H), 4.16-4.19 (d, J = 12.8 Hz, 1H), 3.50-3.56 (t, J = 12.0 Hz, 1H), 2.93-2.99 (m, 2H), 2.77-2.82 (m, 2H), 2.66-2.73 (m, 1H), 1.89 (s, 3H), 1.47-1.49 (d, J = 6.8 Hz, 3H), 1.06-1.08 (d, J = 6.8 Hz, 3H), 0.92-0.94 (d, J = 6.4 Hz, 3H).

Exampe-3: Process for the preparation of Sotorasib (Formula-1)
A mixture of Formula-8 (40 g), N-methyl-2-pyrrolidone (200 mL) and Trifluoroacetic acid (9 g) was stirred for 30 min at 25-30 °C to get a clear solution. Reaction mass was cooled to -5 to 0 °C, added acryloyl chloride (10 g) and stirred for 2 hours at -5 to 0 °C. After completion of reaction (Formula-8 content by HPLC: NMT 1.0%), reaction mass was quenched into aqueous disodium hydrogen phosphate solution (33.63 g of disodium hydrogen phosphate dissolved in 600 mL of DM water) over a period of 6 hours at 40-45 °C and stirred for 2 hours. Thereafter, reaction mass was cooled to 25-30 °C over a period of 2 hours, stirred for 13 hours, filtered the product, washed with DM water (2x400 mL) and suction dried for 3 hours.
A mixture of above wet product, ethanol (280 mL), DM water (80 mL) and trifluoroacetic acid (6.3 g) was stirred for 10 min at 25-30 °C to get a clear solution. Activated carbon (4 g) was added to the solution, stirred for 30 min at 25-30 °C, filtered through hyflo bed and washed with ethanol (40 mL). Filtrate was heated to 40-45 °C, aqueous disodium hydrogen phosphate solution (15.69 g of disodium hydrogen phosphate dissolved in 640 mL of DM water) was added over a period of 4 hours at 40-45 °C and stirred for 2 hours. Thereafter, reaction mass was cooled to 25-30 °C over a period of 1 hour, stirred for 5 hours, filtered, washed with ethanol (40 mL) and DM water (80 mL) solvent mixture and suction dried for 3 hours.
A mixture of above wet product and acetonitrile (200 mL) was heated to 45-50 °C and stirred for 1.5 hours. Thereafter, reaction mass was cooled to 25-30 °C, stirred for 2 hours, filtered, washed with acetonitrile (80 mL) and dried under vacuum for 6 hours at 70-75 °C to get Formula-1 (34 g). Product was micronized and dried under vacuum for 6 hours at 70-75 °C to get Formula-1 as off-white powder (24 g).
Purity: 99.7%; Chiral purity: 100%.
1H NMR (DMSO-d6, 400 MHz): d 10.19 (br, s, 1H), 8.37-8.39 (d, J = 4.8 Hz, 1H), 8.25-8.30 (m, 1H), 7.23-7.29 (q, J = 8.4 Hz, 1H), 7.17-7.18 (d, J = 5.2 Hz, 1H), 6.81-6.88 (m, 1H), 6.66-6.73 (m, 2H), 6.17-6.22 (dd, J = 16.4, 4.4 Hz, 1H), 5.74-5.78 (dd, J = 10.4, 2.4 Hz, 1H), 4.90 (m, 1H), 4.38-4.41 (d, J = 12.4 Hz, 1H), 4.25-4.33 (m, 2H), 3.62-3.69 (m, 1H), 3.25-3.28 (m, 1H), 3.11-3.16 (t, J = 10.8 Hz, 1H), 2.69-2.72 (m, 1H), 1.89 (s, 3H), 1.33-1.35 (d, J = 6.8 Hz, 3H), 1.06-1.08 (d, J = 6.8 Hz, 3H), 0.92-0.94 (d, J = 6.8 Hz, 3H).

Exampe-4: Alternate process for the preparation of Sotorasib (Formula-1)
To a mixture of Formula-8 (10 g) and chloroform (150 mL) was added acrylic anhydride (Formula-9, 2.48 g) at -15 to -10 °C over a period of 1.5 h and stirred for 1.5 h. After completion of reaction (Formula-8 content by HPLC: NMT 1.0%), quenched the reaction mass with aqueous disodium hydrogen phosphate solution (6.95 g of Disodium hydrogen phosphate dissolved in 154 mL of DM water) at below 5 °C and stirred for 30 min. Thereafter, reaction mass temperature was raised to 25-30 °C, stirred for 1 hour, filtered through hyflo bed and washed with chloroform (10 mL). Both layers were separated and organic layer was washed with DM water (2x50 mL), dried over anhydrous sodium sulphate (2.5 g) and washed with chloroform (10 mL). Solvent was concentrated under reduced pressure and co-distilled with acetonitrile (10 mL) at = 45 °C to get a residue. Ethanol (175 mL) and DM water (20 mL) solvent mixture was added to the residue, heated to 70-75 °C and stirred for 10 min. Reaction mass was cooled to 40-45 °C over a period of 1 hour, DM water (160 mL) was added to the mass over a period of 4 hours and stirred for 2 hours at 40-45 °C. Further, reaction mass was cooled to 25-30 °C over a period of 1 hour, stirred for 5 hours, filtered the product, washed with ethanol (10 mL) and DM water (20 mL) solvent mixture and suction dried for 3 hours.
A mixture of above wet product, acetonitrile (100 mL) were heated to 60-65 °C and stirred for 1.5 hours. Thereafter, reaction mass was cooled to 25-30 °C, stirred for 2 hours, filtered, washed with acetonitrile (20 mL) and dried under vacuum for 6 hours at 70-75 °C to get Formula-1 (7 g).
Purity: 97.7%.
,CLAIMS:We Claim:

1. A process for the preparation of Sotorasib compound of formula-1, comprising of:
a) Reacting the 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione of formula-2,

Formula-2
with 2-(2-fluoro-6-methoxyphenyl)-4,4,5.5-tetramethyl-1,3,2-dioxaborolane of formula-3

Formula-3
in presence of a suitable base and catalyst in a suitable solvent to provide 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione of formula-4,

Formula-4
b) treating the compound of formula-4 in-situ with phosphorus oxychloride in presence of a suitable base in a suitable solvent to provide 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl) pyrido[2,3-d]pyrimidine-2-one of formula-5,

Formula-5
c) reacting the compound of formula-5 in-situ with (3S)-3-methyl-1-piperazinecarboxylic acid 1,1-dimethylethyl ester of formula-6,

Formula-6
in presence of a suitable base in a suitable solvent to provide tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, optionally purifying the compound from a suitable solvent to provide pure compound of formula-7,

Formula-7
d) deprotecting and demethylating the compound of formula-7 using a suitable Lewis acid in a suitable solvent to provide 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, optionally purifying the compound from a suitable solvent to provide pure compound of formula-8,

Formula-8
e) treating the compound of formula-8 with acryloyl chloride in presence of an acid in a suitable solvent to provide compound of formula-1, optionally purifying the compound from a suitable solvent to provide pure compound of formula-1.

2. The process as claimed in claim-1, wherein,
In step (a) the catalyst used in the condensation of compound of formula-2 with
compound of formula-3 is Pd(dppf)Cl2. MDC complex or any other palladium derived catalyst.
In step-a), b) & c) the base used is an organic or inorganic base. The organic base is
selected from N,N-diisopropylamine, N,N-diisopropylethylamine, triethylamine, N,N-dimethylamine, trimethylamine, pyridine; the inorganic base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof.
In step (d) & (e) the acid used is selected from organic or inorganic acid. The organic
acid may be selected from methanesulfonic acid, trifluoroacetic acid, triflic acid, p-toluenesulfonic acid, cyanuric acid or any other suitable organic acid. The inorganic acid may be selected from dilute or concentrated acids, hydrochloric acid, ortho phosphoric acid, hydrobromic acid, HBr in acetic acid, boron tribromide (BBr3) or any other suitable inorganic acid.
In step-a, b, c, d & e) the suitable solvent is selected from alcoholic solvents, polar-
aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

3. The process as claimed in claim-1, wherein the preparation of Sotorasib compound of formula-1, comprising of:
a) Reacting the 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione of formula-2 with 2-(2-fluoro-6-methoxyphenyl)-4,4,5.5-tetramethyl-1,3,2-dioxaborolane of formula-3 in presence of aqueous potassium carbonate and Pd(dppf)Cl2.MDC complex in 1,4-dioxane provides 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione of formula-4,
b) treating the compound of formula-4 in-situ with phosphorus oxychloride in presence of diisopropylethylamine in toluene provides 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido [2,3-d]pyrimidine-2-one of formula-5,
c) reacting the compound of formula-5 in-situ with (3S)-3-methyl-1-piperazinecarboxylic acid 1,1-dimethylethyl ester of formula-6 in presence of diisopropylethylamine in isopropyl acetate provides tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, purifying the compound using isopropyl acetate provides pure compound of formula-7,
d) deprotecting and demethylating the compound of formula-7 using boron tribromide (BBr3) and trifluoroacetic acid in dichloromethane provides 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, purifying the compound using aqueous ethanol provides pure compound of formula-8,
e) treating the compound of formula-8 with acryloyl chloride in presence of trifluoroacetic acid in N-methyl-2-pyrrolidone provides compound of formula-1, purifying the compound using aqueous ethanol and trifluoroacetic acid followed by acetonitrile provides pure compound of formula-1.

4. A one-pot process for the preparation of tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d] pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, comprising of:
a) Reacting the 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl] pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione of formula-2 with 2-(2-fluoro-6-methoxyphenyl)-4,4,5.5-tetramethyl-1,3,2-dioxaborolane of formula-3 in presence of aqueous potassium carbonate and Pd(dppf)Cl2. MDC complex in 1,4-dioxane provides 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4-dione of formula-4,
b) treating the compound of formula-4 in-situ with phosphorus oxychloride in presence of diisopropylethylamine in toluene provides 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido [2,3-d]pyrimidine-2-one of formula-5,
c) reacting the compound of formula-5 in-situ with (3S)-3-methyl-1-piperazinecarboxylic acid 1,1-dimethylethyl ester of formula-6 in presence of diisopropylethylamine in isopropyl acetate provides tert-butyl (3S)-4-[6-fluoro-7-(2-fluoro-6-methoxyphenyl)-(1M)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate of formula-7, purifying the compound using isopropyl acetate provides pure compound of formula-7.

5. The process as claimed in claim-4, further comprising the steps of:
a) Deprotecting and demethylating the compound of formula-7 using boron tribromide (BBr3) and trifluoroacetic acid in dichloromethane provides 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, purifying the compound using aqueous ethanol provides pure compound of formula-8,
b) treating the compound of formula-8 with acryloyl chloride in presence of trifluoroacetic acid in N-methyl-2-pyrrolidone provides compound of formula-1, purifying the compound using aqueous ethanol and trifluoroacetic acid followed by acetonitrile provides pure compound of formula-1.

6. The process as claimed in claim-4, further comprising the steps of:
a) Deprotecting and demethylating the compound of formula-7 using boron tribromide (BBr3) and trifluoroacetic acid in dichloromethane provides 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one of formula-8, purifying the compound using aqueous ethanol provides pure compound of formula-8,
b) treating the compound of formula-8 with acrylic anhydride of formula-9 in chloroform provides compound of formula-1, purifying the compound using aqueous ethanol followed by acetonitrile provides pure compound of formula-1.

7. An alternate process for the preparation of Sotorasib compound of formula-1, comprising of treating the compound of formula-8 with acrylic anhydride of formula-9 in chloro solvents such as chloroform provides compound of formula-1, purifying the compound using aqueous ethanol followed by acetonitrile provides pure compound of formula-1.

8. Novel intermediate compounds of Sotorasib having the following structural formulae:

Formula-4 Formula-5

Formula-7
9. The novel intermediate compounds as claimed in claim-8 are useful in the preparation of Sotorasib compound of formula-1.

10. The process as claimed in claim-1, the Sotorasib of formula-1 is having purity more than 99.5% by HPLC.