Novel process for the preparation of {(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-fluoroprop-2-enoyl) piperazin-2-yl} acetonitrile and its intermediates thereof

Abstract

The present invention relates to a novel process for the preparation of {(2S)- 4- [7- (8- chloronaphthalen-1-yl)- 2- {[(2S) -1-methylpyrrolidin-2-yl]- methoxy}- 5, 6, 7, 8-tetrahydro pyrido[3,4-d] pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl) piperazin-2-yl} acetonitrile compound of formula-1 and its intermediates thereof. Formula-1. The present invention also provide novel intermediate compounds of {(2S)- 4- [7- (8- chloronaphthalen-1-yl)- 2- {[(2S) -1-methylpyrrolidin-2-yl]- methoxy}- 5, 6, 7, 8-tetrahydro pyrido[3,4-d] pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl) piperazin-2-yl} acetonitrile.

Description

[0001] Novel process for the preparation of {(2S)-4-[7-(8-chloronaphthalen-l-yl)-2-{[(2S)- l-methylpyrrolidin-2-yl]-methoxy}-5,6,7,8-tetrahydropyrido[3,4-d] pyrimidin-4-yl]- 1 -(2-fluoroprop-2-enoyl) piperazin-2-yl} acetonitrile and its intermediates thereof

[0002] Related Applications:

[0003] This application claims the benefit of priority to our Indian Patent Application Number 202541016057, filed on February 24, 2025, the disclosure of which is incorporated by reference in its entirety.

[0004] Field of the invention:

[0005] The present invention relates to a novel process for the preparation of {(2S)-4-[7-(8-chloronaphthalen- l-yl)-2-{[(2S)- 1-methylp yrrolidin-2-yl] -methoxy }-5, 6,7,8-tetrahydropyrido[3,4-<7| pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl} acetonitrile of formula- 1 and its intermediates thereof.

[0006]

[0007] Background of the invention:

[0008] {(2S)-4-[7-(8-chloronaphthalen-l-yl)-2-{[(2S)-l-methyl pyrrolidin-2-yl]-methoxy } -5,6,7, 8-tetrahydropyrido [3,4-<7]pyrimidin-4-yl] - 1 -(2-fluoroprop-2-enoyl) piperazin-2-yl } acetonitrile of formula- 1 is commonly known as Adagrasib, which is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state. Adagrasibinhibits tumor cell growth and viability in cells harboring KRAS G12C mutations and results in tumor regression in KRAS G12C-mutated tumor.

[0009] Adagrasib is approved in US under the brand name of KRAZATI for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC).

[0010] Process for the preparation of Adagrasib is described in US10689377B2, W02023039020A1, W02023205074A1 and other literatures.

[0011] However, there is always a need exist for alternative preparative routes, which for example involves fewer steps, use reagents that are less expensive and / or easier to handle, consumes smaller amounts of reagents, provide a higher yield of product, have smaller and / or more ecofriendly waste products, and / or provide a higher purity of the final compound of Formula- 1. Hence the inventors of the present invention have developed novel process for the preparation of Adagrasib and its intermediates.

[0012] Brief summary of the invention:

[0013] The present invention is to provide a novel process for the preparation of Adagrasib of formula- 1 and novel intermediate compounds of formula-3, formula-4, formula-6, formula-8, formula-lOa, formula-15, formula-16, formula-17, formula-25a, formula-25b and formula-27.

[0014] Detailed Description of the Invention:

[0015] As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, diisopropyl ether, 1,2-dimethoxy ethane and the like; “ester solvents”such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), formamide, dimethylformamide (DMF), diglyme, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1,2-propanediol (propylene glycol), 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; water or mixtures thereof.

[0016] As used herein the term “base” used in the present invention refers to inorganic bases selected from “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, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide, Rubidium hydroxide, cesium hydroxide, francium hydroxide and the like, “alkaline earth metal carbonates” such as beryllium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, and the like; “alkaline earth metal bicarbonates” such as magnesium bicarbonate, calcium bicarbonate, and the like; “alkaline earth metal hydroxides” such as calcium hydroxide, strontium hydroxide, magnesium hydroxide, barium hydroxide, and the like; “alkyl metals” such as n-butyl lithium and like; “metal hydrides” such as lithium hydride, sodium hydride, potassium hydride and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassium hydrogen phosphate; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and like and “organic bases” selected from but not limited to methyl amine,ethyl amine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, n-methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; “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 amides” such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), “organosilicon bases” such as sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS), potassium hexamethyldisilazide (KHMDS) and the like; or mixtures thereof.

[0017] As used herein the term “acid” in the present invention refers to inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid and like.

[0018] As used herein the term “reducing agent” in the present invention is selected but not limited to Li AIH4, NaAltL, NaBPL, KBH4, mixture of NaBPL & acetic acid, mixture of NaBPL & trifluoroacetic acid, mixture of NaBPL & iodine, mixture of NaBPL & trimethylchlorosilane, mixture of NaBPL & magnesium chloride, mixture of NaBPL & calcium chloride, mixture of NaBPL & one of transition metal chlorides, mixture of sodium borohydride BF3. etherate, sodium cyanoborohydride, sodium triacetoxy borohydride, Aluminium hydride (AIH3), diisobutylaluminium hydride (DIBAL), Vitride {=Sodium bis(2-methoxyethoxy) aluminum hydride}, Lithium Tri-tert-butoxyaluminum Hydride, Tributyl tin Hydride; boranes such as not limited to BHs-tetrahydrofuran, BH dimethyl sulfide;

[0019] As used herein the term “chlorinating agent” in the present invention is selected but not limited to phosphorus oxychloride, phosphorus pentachloride,chlorine.

[0020] As used herein the term of “amino protecting group” can be selected from methoxymethyl [MOM], methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, methoxyisopropyl, ethoxy isobutyl or 4,4'-dimethoxy; trifluoroacetyl; 9H-fluoren-9-ylmethoxycarbonyl (FMOC); alkyloxycarbonyl such as t-butyloxycarbonyl; or any other suitable protecting group.

[0021] As used herein the term of Amine -protecting groups as defined as Amine-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule. Examples of an amine -protecting agent include, but are not limited to, methoxy methyl chloride, methoxyethyl chloride, methoxypropyl chloride, ethoxymethyl chloride, ethoxyethyl chloride, methoxyisopropyl chloride; C₁-C₆ aliphatic acid chlorides or anhydrides, C₆-C₁₄ arylcarboxylic acid chlorides or anhydrides, t-butyl chloroformate, di-tert-butyl dicarbonate, butoxycarbonyl oxyimino-2-phenylacetonitrile, t-butoxycarbonyl azide, t-butyl fluoroformate, fluorenyl methoxy carbonyl chloride, fluorenylmethoxy carbonyl azide, fluorenylmethoxy carbonyl benzotriazol- 1-yl, (9-fluorenyl methoxy carbonyl)succinimidylcarbonate, fluorenyl methoxy carbonyl pentafluoro phexoxide, trichloroacetyl chloride, methyl-, ethyl-, trichloro methyl-chloroformate, and other amine protecting agents known in the art. Examples of such known amine -protecting agents are found in T. W. Green, P. G. M. Wuts, " Protective Groups in Organic Synthesis, Second Edition," Wiley-lnterscience, New York, pages 385-397, 1991.

[0022] As used herein the term “coupling agent” used in the present invention can be selected from but not limited to N, N' -dicyclohexylcarbodiimide (DCC), Propane phos phonic acid anhydride (T3P), N, N"-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (EDC. HC1), N, N"-carbonyl diimi dazole (CDI), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HBTU), IH-benzotriazolium-l-[bis (dimethyl amino) methylene]-5-chloro-hexafluorophosphate(l)-3-oxide (HCTU), (benzo triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), benzotriazol- 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), l-hydroxy-7-azatriazole (HO At), 1 -hydroxy benzotriazole (HOBt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), O-(benzotriazol-l-yl)-N, N, N', N'-tetramethyluronium tetra fluo roborate (TBTU), N-hydroxy succinamide (HOSu), N-hydroxy sulfosuccinimide (Sulfo-NHS), ethyl cyanohydroxy iminoacetate (Oxyma), 7-Azabenzotriazol-l-yl oxy)tripyrrolidinophosphonium hexafluoro phosphate (PyAOP), N, N, N', N' -Tetra methyl-O-(N-succinimidyl)uranium tetrafluoroborate (TSTU), alkyl or aryl chloro formates such as ethyl chloroformate, benzylchloroformate, DPPA, thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous penta chloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), methane sulfonyl chloride and the like; optionally in combination with base or mixtures thereof.

[0023] As used herein the term “oxidizing agent agent” used in the present invention can be selected from but not limited to peracid, oxone, bleach, hydrogen peroxide, NaIO₄, perborate, percarbonate, urea hydrogen peroxide, meta-Chloroperbenzoic acid (mCPBA), osmiumtetroxide, hydrogenperoxide, potassium permanganate, magnesium chlorate, silver chlorate, peroxymonosulfuric acid, peracetic acid, dimethyl dioxirane, sodium perborate, nitrous oxide, sodium hypochlorite, peroxy acetic acid, pyridinium chloroformate, pyridinium dichromate, chromium trioxide, TEMPO, TPAP, potassium dichromate and the like

[0024] The first embodiment of the present invention provides a process for the preparation of Adagrasib of formula- 1, comprising one or more of the following steps:

[0025] a) reacting the compound of formula-2 with urea to provide the compound of formula-3,

[0026] b) treating the compound of formula-3 with a chlorinating agent to provide the compound of formula-4,

[0027] c) reacting the compound of formula-4 with compound of formula-5 or its salt toprovide the compound of formula-6,

[0028] d) reacting the compound of formula-6 with compound of formula-7 or its salt to provide the compound of formula- 8,

[0029] e) reacting the compound of formula-8 with compound of formula-9 to provide Adagrasib of formula- 1.

[0030] In the first aspect of the first embodiment, the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0031] In the second aspect of the first embodiment, wherein the reaction in steps-a), c), e) can be carried out in presence of a base which are same as defined above; chlorinating agent in step-b) is same as defined above.

[0032] In the third aspect of the first embodiment, wherein the reaction in step-d) can be carried out in presence of a coupling agent which is same as defined above.

[0033] In the fourth aspect of the first embodiment, wherein the reaction in steps-a) to step-e) can be carried out in a solvent which are same as defined above.

[0034] The second embodiment of the present invention provides a process for the preparation of Adagrasib of formula- 1, comprising one or more of the following steps:

[0035] a) protecting the compound of formula-6 with an amine protecting agent to provide the compound of formula- 10,

[0036] b) reacting the compound of formula- 10 with compound of formula-9 to provide formula- 11.

[0037] In the first aspect of the second embodiment, wherein the protecting agent in step-a) is same as defined above; the reaction in step-b) can be carried out in presence of a base in a solvent which are same as defined above.

[0038] In the second aspect of the second embodiment, wherein the compound of formula-6 can be prepared according to the first embodiment of the present invention.

[0039] In the third aspect of the second embodiment, wherein the compound offormula- 11 further converted into Adagrasib of formula- 1 by the process described in the present invention or the process known in the literature such as US10689377B2, W02023039020A1.

[0040] In the fourth aspect of the second embodiment, wherein the reaction in steps-a) to step-b) can be carried out in a solvent which are same as defined above.

[0041] In the fifth aspect of the second embodiment, the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0042] First and second embodiments of the present invention schematically shown as below:

[0043] Scheme 1

[0044]

[0045] The third embodiment of the present invention provides a process for the preparation of Adagrasib of formula- 1 comprising one or more of the following steps: a) reacting the compound of formula-2 with compound of formula- 13 to provide the compound of formula- 14,

[0046] b) converting the compound of formula- 14 to the compound of formula- 15, c) reacting the compound of formula- 15 with compound of formula-5 or its salt to provide the compound of formula- 16,

[0047] d) converting the compound of formula- 16 to the compound of formula- 17, e) oxidation of the compound of formula- 17 to provide a compound of formula- 18, f) reacting the compound of formula- 18 with compound of formula-9 to provide the compound of formula- 11, and converting the compound of formula- 11 to Adagrasib of formula- 1.

[0048] In the first aspect of the third embodiment, wherein the conversion of compound of formula- 11 to Adagrasib of formula- 1 by the process described in the present invention or the process known in the literature such as US10689377B2, W02023039020A1.

[0049] In the second aspect of the third embodiment, wherein the reaction in steps-b), c), f) can be carried out in presence of a base which are same as defined above.

[0050] In the third aspect of the third embodiment, wherein the oxidation in step e) can be performed by using an oxidizing agents selected from but not limited to peracid (such as meta-chloroperbenzoic acid or peracetic add), oxone, bleach, hydrogen peroxide and urea / hydrogen peroxide.

[0051] In the fourth aspect of the third embodiment, wherein in step-b) the conversion of compound of formula- 14 to compound of formula- 15 by using the protecting agents which are selected from Triflic anhydride, Methane sulfonyl chloride and 2-nitrobenzene- 1 -sulfonyl chloride.

[0052] In the fifth aspect of the third embodiment, wherein the reaction in step-a) to step-f) can be carried out in a solvent which are same as defined above.

[0053] In the sixth aspect of the third embodiment, wherein the different reactionsteps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0054] In the seventh aspect of the third embodiment, wherein the process for the preparation of Adagrasib of fomrula- 1, comprising,

[0055] a) deprotecting the compound of formula 11 to obtain a compound of formula- 12,

[0056]

[0057] b) reacting with the compound of fomrula- 12 with 2-fluoroacrylic acid or its salts or its derivatives to provide Adagrasib of fomrula- 1.

[0058] The fourth embodiment of the present invention provides a process for the preparation of Adagrasib of formula- 1 comprising one or more of the following steps: a) deprotecting a compound of formula- 18 to provide a compound of formula- 19, b) reacting compound of formula- 19 with a compound of formula-7 or its salt to provide a compound of formula-20,

[0059] c) reacting the compound of formula-20 with compound of formula-9 to afford Adagrasib of formula- 1.

[0060] In the first aspect of the fourth embodiment, wherein the compound of formula- 18 can be prepared according to the third embodiment of the present invention.

[0061] In the second aspect of the fourth embodiment, wherein the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0062] In the third aspect of the fourth embodiment, wherein in step-a) thedeprotecting of compound of formula- 19 can be carried out in presence of acid which is same as defined above.

[0063] In the fourth aspect of the fourth embodiment, wherein the reaction in step b) can be carried out in presence of a coupling agent which are same as defined above.

[0064] In the fifth aspect of the fourth embodiment, wherein the reaction in step c) can be carried out in presence of a base which is same as defined above.

[0065] In the sixth aspect of the fourth embodiment, wherein the reaction in steps-a) to step-c) can be carried out in a solvent which are same as defined above.

[0066] In the seventh aspect of the fourth embodiment, the compound of formula- 11 further converted to Adagrasib of formula- 1 by the process described in the present invention or the process known in the literature such as US10689377B2, W02023039020A1.

[0067] Third and fourth embodiments of the present invention schematically shown as below:

[0068] Scheme 2

[0069]

[0070] The fifth embodiment of the present invention provides a novel process for the preparation of intermediate compound of formula-2 comprising one or more of the following steps:

[0071] a) reductive amination of compound of formula-21 with compound of formula-22 to provide a compound of formula-23,

[0072] b) reacting compound of formula-23 with compound of formula-24 to provide a compound of formula-27,

[0073] c) converting the compound of formula-27 to a compound of formula-2.

[0074] In the first aspect of the fifth embodiment, the compound of formula-2 further converted to Adagrasib of formula- 1 by the process described in the present invention or the process known in the literature such as US10689377B2, W02023039020A1.

[0075] In the second aspect of the fifth embodiment, wherein the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0076] In the third aspect of the fifth embodiment, wherein in step-a) the reductive amination can be carried out by using the reducing agents which are defined same as above.

[0077] In the fourth aspect of the fifth embodiment, wherein the reaction in steps-b) and c) can be carried out in presence of a base.

[0078] In the fifth aspect of the fifth embodiment, wherein the reaction in steps-a) to step-c) can be carried out in a solvent which are same as defined above.

[0079] The sixth embodiment of the present invention provides a novel process for the preparation of intermediate compound of formula-2 comprising one or more of the following steps:

[0080] a) reacting a compound of formula-21 with compound of formula-24 to provide a compound of formula-25,

[0081] b) reacting compound of formula-25 with compound of formula-26 to provide the compound of formula-27,c) converting the compound of formula-27 to a compound of formula-2.

[0082] In the first aspect of the sixth embodiment, the compound of formula-2 further converted to Adagrasib of formula- 1 by the process described in the present invention or the process known in the literature such as US10689377B2, W02023039020A1.

[0083] In the second aspect of the sixth embodiment, wherein the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0084] In the third aspect of the sixth embodiment, wherein the reaction in steps-a) to c) can be carried out in presence of a base in a solvent or mixture of solvents.

[0085] Fifth and sixth embodiments of the present invention schematically shown as below:

[0086]

[0087] The seventh embodiment of the present invention provides novel intermediate compounds of Adagrasib of formula- 1 represented by the following structural formulae:Boc

[0088] Formula-3 Formula-4

[0089]

[0090] Formula-25a Formula- 15

[0091]

[0092] Wherein R= C1-C6 alkyl group; R1= C1-C6 alkyl group and

[0093] Pi = amine protecting group; P2= Tf, Ms, or Aryl substituted sulfonyl groupIn an aspect of the seventh embodiment, the novel intermediate compounds are useful in the preparation of Adagrasib of formula- 1.

[0094] The eighth embodiment of the present invention provides pure Adagrasib of formula- 1 having the purity greater than 99% by HPLC and total impurities less than 1.0% (w / w), preferably less than 0.5% and more preferably less than 0.15%. further any unknown impurity is controlled less than 0.10%.

[0095] The ninth embodiment of the present invention provides Adagrasib obtained is in crystalline form or amorphous form.

[0096] The tenth embodiment of the present invention provides amorphous form of Adagrasib having particle size distribution as characterized by 90% particles having particle size (D90) less than about 500 pm, preferably less than about 400 pm, 50% particles having particle size (D50) less than about 250 pm, preferably less than about 200 pm and 10% particles having particle size (D10) less than about 100 pm, preferably less than about 75 pm.

[0097] The eleventh embodiment of the present invention provides crystalline form of Adagrasib has particle size distribution as characterized by 90% particles having particle size (D90) less than about 100 pm, preferably less than about 50 pm, 50% particles having particle size (D50) less than about 50 pm, preferably less than about 20 pm, and 10% particles having particle size (D10) less than about 15 pm, preferably less than about 10 pm.

[0098] The twelfth embodiment of the present invention provides Adagrasib or its salts can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronizationmay be performed before drying or after drying of the product.

[0099] The thirteenth embodiment of the present invention provides a pharmaceutical composition comprising Adagrasib of formula- 1 obtained according to the present invention and at least one pharmaceutically acceptable excipient.

[0100] As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0101] The invention also encompasses pharmaceutical compositions comprising Adagrasib of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0102] The term “pharmaceutically acceptable excipients” selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatine, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glycerol dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures thereof; suitable disintegrants that can be include magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low- substitutedhydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene -polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta-cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl-beta-cyclodextrin.

[0103] The fourteenth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of Adagrasib of Formula- 1 and one or more pharmaceutically acceptable excipients.

[0104] The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.

[0105] Examples:

[0106] Example-1: Preparation of 7-(8-chloronaphthalen-l-yl)-2-(isopropylthio)-5, 6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-ol of formula-14a

[0107] Isopropyl iodide (134 g) was added to a pre-cooled mixture of Thiourea (55 g) and isopropyl alcohol (1500 ml) at 10-20°C. Heated the reaction mixture to 75°C to 85°C and stirred the reaction mixture. Distilled off the reaction mixture under reduced pressure. Dissolved the obtained compound in 2-methyl tetrahydrofuran (200 ml) and added to the solution of Ethyl l-(8-chloronaphthalen-l-yl)-3-oxopiperidine-4-carboxylate of formula-2a (200 g) in 2-methyl tetrahydrofuran (1800 ml) at 25-35°C and cooled to -5°C to 5°C. N, N-diisopropylethylamine (120 g) was added to the above reaction mixture and stirred at the same temperature. Methanesulphonic acid (70 g) was added to the reaction mixture. Heated the reaction mixture to 45-55°C andstirred at the same temperature. Aqueous sodium sulphite solution (80 g in water) was added to the above reaction mixture and stirred. Separated the both organic and aqueous layers. Distilled off the solvent from the organic layer under reduced pressure. Acetonitrile was added to the obtained compound and cooled the reaction mixture to -5°C to 5°C, stirred. Filtered the solid and washed then dried to get the title compound. Yield: 218.4 g.

[0108] Example-2: Preparation of (S)-2-(4-(7-(8-chloronaphthalen-l-yl)-2-(isopropyl thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile of formula-16a

[0109] Diisopropylethylamine (167 g), Dimethylaminopyridine (1.2 g) were added to the pre-cooled mixture of the compound of formula- 14a (80 g) and dichloromethane (1000 ml) at -5°C to 5°C. A solution of 2-Nitrobenzene sulfonyl chloride (149 g) in dichloromethane (200 ml) was added to the above reaction mixture. Raised the temperature of the reaction mixture to 25°C to 30°C and stirred at the temperature. Water was added to the reaction mixture. Separated the organic layer and aqueous layer. The aqueous layer was extracted with dichloromethane. Combined the organic layers and distilled off the solvent under reduced pressure to get residue. The obtained compound was dissolved in dimethylacetamide (200 ml) and cooled to 10-20°C. The mixture of dimethylacetamide (600 ml), 2-(Piperazin-2-yl) acetonitrile di hydrochloride of formula-5a (133 g) and diisopropylethylamine (130 g) was added to the above mixture and stirred. Water was added to the above reaction mixture. Seed material (1 g) of title compound was added to the reaction mixture. Water (2600 ml) was added to the reaction. Filtered the precipitated solid and washed with dimethylacetamide and water. Slurried the obtained compound in the mixture of water and acetonitrile, filtered, washed with acetonitrile and dried to get title compound. Yield: 237.0 g.

[0110] Example-3: Preparation of (S)-tert-butyl 4-(7-(8-chloronaphthalen-l-yl)-2-(isopropyl thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl) piperazine-l-carboxylate of formula-17aDi-tert-butyldicarbonate (265 g) was slowly added to the solution of the compound of formula- 16a (200 g) in Dichloromethane (2000 ml) at 25°C to 35°C. Water added to the reaction mixture and the resulting layers were separated. The aqueous layer was subsequently extracted with dichloromethane. Combined the organic layers and then washed with aqueous sodium chloride solution. The organic layer was subjected to distillation under reduced pressure. The obtained compound was slurried in n-heptane, filtered and dried to get title compound. Yield: 130 g.

[0111] Example-4: Preparation of (S)-tert-butyl 4-(7-(8-chloronaphthalen-l-yl)-2-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyano methyl)piperazine-l-carboxylate of formula-18a

[0112] The solution of meta-chloro per benzoic acid (139 g) in dichloromethane (240 ml) added to the pre-cooled solution of the compound of formula- 17a (120 g) in dichloromethane (1200 ml) at 0-5°C and stirred at the same temperature. Water was added to the reaction mixture and the temperature was raised to 25-30°C. Aqueous sodium bicarbonate solution added to the reaction mixture and layers were separated. The organic layer was sequentially washed with aqueous sodium bicarbonate solution, aqueous sodium thiosulfate solution, and followed by with aqueous sodium chloride solution. The organic layer was distilled off under reduced pressure to form a residue, which was then co-distilled with petroleum ether. The obtained compound was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluents to get the title compound. Yield: 126.47 g.

[0113] Example-5: Preparation of (S)-tert-butyl 4-(7-(8-chloronaphthalen-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate of formula-lla

[0114] (2S)-1 -methyl pyrrolidine-2-ylmethanol of formula-9 (6 g) was added to the mixture of the compound of formula- 18a (24 g) and 2-MeTHF (240 ml) at 25-30°C. Sodium hydride (4.6 g) was added lot-wise to the reaction mixture and stirred. The reaction mixture was cooled to 10°C to 15°C, quenched with pre-cooled water. Separated the organic layer and aqueous layer. The aqueous layer was then extracted with 2-MeTHF. Combined the organic layers and water added to it. The mixture was acidified with aqueous HC1 solution, and layers separated. 2-MeTHF added to the obtained aqueous layer and basified the mixture with aqueous sodium hydroxide solution. Separated the layers and the aqueous layer extracted with 2-MeTHF. Combined the organic layers, washed with aqueous sodium chloride solution and distilled off the solvent. The obtained compound was purified by silica gel column chromatography using a mixture of Ethyl acetate and petroleum ether to get the title compound. Yield: 14.2 g.

[0115] Example-6: Preparation of 2-((S)-4-(7-(8-chloronaphthalen-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) piperazin-2-yl)acetonitrile of formula-12

[0116] Trifluoroacetic acid (20 ml) was added to the mixture of compound of formula-1 la (10 g) and dicloromethane (100 ml) at 25-30°C and stirred. The reaction mixture was added to the pre cooled aqueous sodium bicarbonate solution at 10°C to 15°C. Separated the organic layer and aqueous layer, and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium chloride solution followed by distilled off the solvent to get title compound.

[0117] Yield: 8.42 g.

[0118] Example-7: Preparation Adagrasib of fomrula-1

[0119] Propanephosphonic acid anhydride (T3P) (21 g) was added to the pre-cooled mixture of sodium 2-fluoroacrylate (6.5 g) and Acetonitrile (49 ml) at 10°C to 20°C and stirred. The mixture of compound of fomrula-12 (7 g) and Acetonitrile (49 ml) added to the above reaction mixture and stirred. The mixture was basified with aqueous solution of potassium carbonate. Separated the organic layer and aqueous layer, and the aqueous layer was extracted with 2-methyl tetrahydrofuran. Combined the organic layers and distilled off the solvent under reduced pressure and co-distilled with isopropyl alcohol. The obtained compound was dissolved in isopropyl alcohol and then n-heptane was added. Seed material was added to the obtained mixture and stirred. Filtered the precipitated solid and dried to get title compound. Yield: 3.5 g.

Claims

CLAIMS1. A process for the preparation of Adagrasib of formula- 1,comprising one or more of the following steps:a) reacting a compound of formula-2 with a compound of formula- 13 to obtain a compound of formula- 14NHFormula- 13 Formula- 14, b) converting the compound of formula- 14 to a compound of formula- 15Formula- 15,c) reacting the compound of formula- 15 with a compound of formula-5 or a salt thereof to obtain a compound of formula- 16Formula- 16,d) converting the compound of formula- 16 to a compound of formula- 17Formula- 17,e) oxidizing the compound of formula- 17 to obtain a compound of formula- 18Formula- 18,f) reacting the compound of formula- 18 with a compound of formula-9 to obtain a compound of formula- 11Formula-9and converting the compound of formula- 11 to Adagrasib of formula- 1; wherein R=C₁-C₆ alkyl group; R₁=C₁-C₆ alkyl group; Pi = amine protecting group; P2= Tf, Ms, or Aryl substituted sulfonyl group.

2. The process as claimed in claim 1, wherein the process for the preparation of Adagrasib of formula- 1, comprising,a) deprotecting the compound of formula 11 to obtain a compound of formula- 12Formula- 12, b) reacting with the compound of formula- 12 with 2-fluoroacrylic acid or its salts or its derivatives to provide Adagrasib of formula- 1.

3. The process as claimed in claim 1, wherein steps b), c), and f) are carried out in the presence of a base selected from inorganic bases, organic bases, alkali metal alkoxides, alkali metal amides, organosilicon bases, or mixtures thereof.

4. The process as claimed in claim 1, wherein step e) is carried out in presence of an oxidizing agent selected from meta-chloroperbenzoic acid, hydrogen peroxide, peracids, oxone, sodium periodate, sodium hypochlorite, TEMPO, TPAP, potassium permanganate, or mixtures thereof.

5. The process as claimed in claim 1, wherein step b) comprises conversion of the compound of formula- 14 to the compound of formula- 15 using a protecting or activating agent selected from trifluoromethanesulfonic anhydride, methane sulfonyl chloride, or 2-nitrobenzene- 1 -sulfonyl chloride.

6. The process as claimed in claim 1, wherein steps a) to f) are carried out in presence of a solvent selected from hydrocarbons, ethers, esters, polar aprotic solvents, chlorinated solvents, ketones, nitriles, alcohols, water, or mixtures thereof.

7. The process as claimed in claim 1, wherein Adagrasib of formula- 1 having a purity greater than 99.0% by HPLC, with total impurities less than 1.0% (w / w).

8. The Adagrasib as claimed in claim 1, wherein the Adagrasib is obtained in a crystalline form or an amorphous form.

9. Amorphous form of Adagrasib having particle size distribution as characterized by 90% particles having particle size (D90) less than about 500 µm, 50% particles having particle size (D50) less than about 250 µm, and 10% particles having particle size (D10) less than about 100 µm.

10. Crystalline form of Adagrasib having particle size distribution as characterized by 90% particles having particle size (D90) less than about 100 µm, 50% particleshaving particle size (D50) less than about 50 pm, and 10% particles having particle size (D10) less than about 15 µm.

11. Intermediate compounds of Adagrasib, represented by compounds of formulae - 15, 16, 17 and 18wherein R= C₁-C₆ alkyl group; R₁= C₁-C₆ alkyl group and; P₁ = amine protecting group; P₂= Tf, Ms, or Aryl substituted sulfonyl group.

12. The intermediates as claimed in claim 11, represented by compounds of formulae - 15a, 16a, 17a and 18a13. The intermediates as claimed in claim 11, wherein said intermediates are useful for the preparation of Adagrasib of Formula- 1.

14. The pharmaceutical composition comprising of Adagrasib of Formula- 1 obtained according any of preceding claims and at least one pharmaceutically acceptable excipient.

15. A method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of Adagrasib of Formula- 1 according any of preceding claims and one or more pharmaceutically acceptable excipients.

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