An improved process for the preparation of obicetrapib and its pharmaceutically acceptable salts thereof

Abstract

The present invention relates to a process for the preparation of Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof The present invention also relates to a process for the preparation of Obicetrapib hemicalcium of Formula I' from Obicetrapib of Formula I via Obicetrapib sodium of Formula IA,

Description

[0001] AN IMPROVED PROCESS FOR THE PREPARATION OF OBICETRAPIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF RELATED PATENT APPLICATION

[0002] This application claims the priority to and benefit of Indian Provisional Patent Application No. 202541036088 which was filed on 14thApril 2025; the disclosures of which are incorporated herein by reference.

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to an improved process for the preparation of Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0005]

[0006] BACKGROUND OF THE INVENTION

[0007] Obicetrapib (also known as AMG-899) is chemically known as (2R,4S)-4-[[3,5-bis(trifluoromethyl)benzyl][5-(3-carboxypropoxy)pyrimidin-2-yl]amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester. The molecular formula is C32H31F9N4O5 and the molecular weight is 722.60. The structural Formula is:

[0008]

[0009] Obicetrapib is a next generation selective oral cholesteryl ester transfer protein (CETP) inhibitor as previously been shown that potently decreases low-density lipoprotein-cholesterol (LDL-C) as well as increases high-density lipoprotein-cholesterol (HDL-C).

[0010] Obicetrapib was initially developed by Amgen as AMG-899 and was abandoned in 2017. In 2020, Amgen licensed the drug to New Amsterdam Pharma.

[0011] Obicetrapib was disclosed in WO 2005095409 A2 (Tanabe Seiyaku Co., Ltd.). This publication (WO’409) discloses the process for the preparation Obicetrapib of Formula I, by reacting compound of Formula 2 with compound of Formula 3 in the presence of DMF at 150 °C, the residue was purified by column chromatography to obtain compound of Formula 4, further coupling with compound of Formula 5 in the presence of DMF and NaH, the residue was purified by column chromatography to obtain compound of Formula 6. Reacting compound of Formula 6 with Pd(dppf)Ch, AcOK, and Bipini in the presence of DMSO, the residue was dissolved in THF and thereto is added dropwise a 30% aqueous H2O2 solution, further saturated aq. NaiSiOs solution was added to the mixture, the residue was purified by silica gel column chromatography to obtain compound of Formula 7, which is coupling with compound of Formula 8 in the presence of DMF and K2CO3, the residue was purified by silica gel column chromatography to obtain compound of Formula 9. Hydrolysis of compound of Formula 9 in the presence of EtOH and aqueous NaOH solution, the residue was purified by silica gel column chromatography to obtain Obicetrapib of Formula I. The process disclosed in given below schematically.

[0012]

[0013] Formula 4

[0014] DMF, NaH Step-II Purified by column chromatography

[0015]

[0016] The process of prior-art proceeds with longer hours of maintenance and involves purification by column chromatography, which makes it is not suitable to perform in large-scale industrial production.

[0017] From the foregoing, it is apparent that the reported methods for the preparation of Obicetrapib compound of Formula I have many disadvantages, like tedious workup process, required longer reaction time and column chromatography for purification, which affect the overall yield of the final product.

[0018] Therefore, there is an urgent need for an alternative process for the preparation of the Obicetrapib compound of Formula I and its pharmaceutically acceptable salts thereof, employing it without any impact on the environment and cost-effective process by eliminating column chromatography with high purity and high yield which overcomes the drawbacks of the prior art process.

[0019] OBJECTIVE OF THE INVENTION

[0020] The main objective of the present invention is to provide an improved process for the preparation of Obicetrapib of Formula I and its pharmaceutically acceptable saltsthereof, which is industrially viable and suitable for large scale operations.

[0021] In another objective of the present invention is to provide an amorphous form of Obicetrapib sodium of Formula IA,

[0022]

[0023] which is used in the preparation of Obicetrapib hemicalcium of Formula I’.

[0024]

[0025] Formula I'

[0026] SUMMARY OF THE INVENTION

[0027] Accordingly, the present invention provides an improved process for the preparation of Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0028] In one aspect, the present invention provides a process for the preparation of Obicetrapib of Formula I,

[0029]

[0030] which comprises:i. desalifying compound of Formula II,

[0031]

[0032] Formula II

[0033] in the presence of a suitable base and a suitable solvent to provide a compound of Formula II’ (in-situ);

[0034]

[0035] Formula II'

[0036] ii. reacting the compound of Formula IF ( in-situ ) with a compound of Formula III,

[0037]

[0038] Formula III

[0039] •wherein X = Halogen

[0040] in the presence of a suitable solvent, optionally with a suitable base,

[0041] (OR)

[0042] desalifying compound of Formula IV’ with a suitable base in the presence of a suitable solvent,

[0043]

[0044] Formula IV

[0045] to provide a compound of Formula IV;

[0046]

[0047] Formula IViii. reductively aminating the compound of Formula IV with a compound of Formula V,

[0048]

[0049] Formula V

[0050] in the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,

[0051]

[0052] followed by reacting with a suitable reducing agent to provide a compound of Formula VII;

[0053]

[0054] iv. coupling the compound of Formula VII with a compound of Formula VIII,

[0055]

[0056] Formula VIII

[0057] •wherein Pg = Protecting group; X = Halogen

[0058] in the presence of a suitable base, a suitable solvent and a suitable catalyst to provide a compound of Formula IX,

[0059]

[0060] wherein Pg = Protecting group

[0061] v. deprotecting the compound of Formula IX with a suitable deprotecting agent in the presence of a suitable solvent to provide Obicetrapib of Formula I; vi. optionally, converting the Obicetrapib of Formula I to its pharmaceutically acceptable salts thereof; and

[0062] vii. optionally purifying Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0063] In another aspect, the present invention provides a process for the preparation of compound of Formula IV,

[0064]

[0065] Formula IV

[0066] which comprises:

[0067] i. desalifying compound of Formula II,

[0068]

[0069] Formula II

[0070] in the presence of a suitable base and a suitable solvent to provide a compound of Formula II’ (in-situ)',

[0071]

[0072] Formula II'

[0073] ii. reacting the compound of Formula II’ (in-situ) with a compound of Formula III,

[0074]

[0075] Formula III

[0076] wherein X = Halogen

[0077] in the presence of a suitable solvent, optionally with a suitable base, (OR)

[0078] desalifying compound of Formula IV’ with a suitable base in the presence of a suitable solvent,

[0079]

[0080] Formula IV'

[0081] to provide a compound of Formula IV; and

[0082] iii. converting the compound of Formula IV into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0083] In another aspect, the present invention provides a process for the preparation of compound of Formula VII,

[0084]

[0085] which comprises:

[0086] i. reductively aminating the compound of Formula IV,

[0087]

[0088] Formula IV

[0089] with a compound of Formula V,

[0090]

[0091] Formula V

[0092] in the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,

[0093]

[0094] followed by reacting with a suitable reducing agent to provide a compound of Formula VII;

[0095] ii. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0096] In another aspect, the present invention provides a process for the preparation of compound of Formula IX,

[0097]

[0098] wherein Pg = Protecting group

[0099] which comprises:i. coupling compound of Formula VII,

[0100]

[0101] with a compound of Formula VIII,

[0102]

[0103] Formula VIII

[0104] wherein Pg = Protecting group; X = Halogen

[0105] in the presence of a suitable base, a suitable solvent and a suitable catalyst to provide a compound of Formula IX; and

[0106] ii. converting the compound of Formula IX into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0107] In another aspect, the present invention provides a process for the preparation of compound of Formula VII,

[0108]

[0109] which comprises:

[0110] i. reacting compound of Formula X,

[0111]

[0112] Formula X

[0113] with a compound of Formula III,

[0114]

[0115] Formula III

[0116] wherein X = Halogen

[0117] in the presence of a suitable base and a suitable solvent to provide a compound of Formula XI;

[0118]

[0119] Formula XI

[0120] ii. reductively aminating the compound of Formula XI with a compound of Formula XII,

[0121]

[0122] in the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,

[0123]

[0124] followed by reacting with a suitable reducing agent to provide a compound of Formula VII; and

[0125]

[0126] iii. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0127] In another aspect, the present invention provides a process for the preparation of compound of Formula VII,

[0128]

[0129] which comprises:

[0130] i. reacting compound of Formula X,

[0131]

[0132] Formula X

[0133] with a compound of Formula XII,

[0134]

[0135] Formula XII

[0136] in the presence of a suitable solvent to provide an imine compound of Formula XIII;

[0137]

[0138] ii. reacting the compound of Formula XIII with a compound of Formula III,

[0139]

[0140] Formula III

[0141] wherein X = Halogen

[0142] in the presence of a suitable base and a suitable solvent to provide a compound of Formula VI;

[0143]

[0144] iii. reducing the compound of Formula VI with a suitable reducing agent in the presence of a suitable solvent to provide a compound of Formula VII; and iv. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0145] In another aspect, the present invention provides a process for the preparation of Obicetrapib sodium of Formula IA,

[0146]

[0147] which comprises:

[0148] i. dissolving crude Obicetrapib of Formula I in a suitable solvent or mixture of solvents at a suitable temperature;

[0149] ii. adding sodium source to the step i) solution at a suitable temperature;

[0150] iii. isolating Obicetrapib sodium of Formula IA.In another aspect, the present invention provides an amorphous form of Obicetrapib sodium of Formula IA,

[0151]

[0152] In another aspect, the present invention provides a process for the preparation of Obicetrapib hemicalcium of Formula I’,

[0153]

[0154] Formula I'

[0155] which comprises:

[0156] i. treating amorphous form of Obicetrapib sodium of Formula IA,

[0157]

[0158] with a suitable calcium source in a suitable solvent or mixture of solvents at a suitable temperature;

[0159] ii. isolating pure Obicetrapib hemicalcium of Formula I’.In another aspect, the present invention provides a process for the purification of Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof, which comprises:

[0160] i. dissolving crude Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof in a suitable solvent or a mixture of a suitable solvents at a suitable temperature;

[0161] ii. heating the step i) solution at a suitable temperature; and

[0162] iii. isolating the pure Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0163] In another aspect, the present invention provides a process for the preparation of Obicetrapib or its sodium / calcium salt obtained in the processes are having free of below impurities:

[0164]

[0165] BRIEF DESCRIPTION OF THE DRAWINGS Figure-1: Illustrates the PXRD pattern of an amorphous form of Obicetrapib sodium of Formula IA.

[0166] DETAILED DESCRIPTION OF THE INVENTION

[0167] The following description with accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.

[0168] Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein may be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.

[0169] The terms and words used in the following description and claims are not limited to the bibliographical meanings but are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the scope of the invention as defined by the appended claims and their equivalents.

[0170] It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0171] Features that are described and / or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and / or in combination with or instead of the features of the other embodiments.

[0172] It should be emphasized that the term “comprises / comprising” when used in this specification is taken to specify the presence of stated features, steps or componentsbut does not preclude the presence or addition of one or more other features, steps, components or groups thereof.

[0173] The suitable “solvent” as used in the present invention is selected from but not limited to “alcohol solvents” such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; “halogenated solvents” such as dichloromethane, dichloroethane, chloroform, chlorobenzene, bromobenzene, carbon tetrachloride, and the like; “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet. ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile, and the like; “amide solvents” such as N, N-dimethylformamide, N, N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone; “polar solvents” such as water; formic acid, acetic acid and the like; or mixtures thereof.

[0174] The “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropyl amide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like; or mixtures thereof.

[0175] The term “suitable catalyst” as used in the present invention is selected from but not limited to [l,l'-bis(diphenylphosphino) ferrocene] dichloro palladium (II) ([Pd(dppf)Cl2]), [l,l'-bis(di-tert-butylphoshino) ferrocene] dichloro palladium(I) ([Pd(dtbpf)Cl2]) tetrakis (triphenyl phosphine) palladium(O) (Pd(PPh3)4), bromo(tri-tert-butylphosphine) palladium(I) dimer ([Pd(p-Br)(t-BusP)]2), bis(tri-tert-butylphosphine)palladium(O) ([Pd(tBusP)]2), palladium(II) acetate (Pd(OAc)2), palladium(II) chloride (PdCh), bis (benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Cl2]), bis(triphenylphosphine) palladium(II) dichloride ([Pd(PPh3)2Cl2]), bis (acetonitrile)palladium(II) dichloride ([Pd(NCMe)2Cl2]), bis[di-tert-butyl(4-dimethyl aminophenyl)phosphine] dichloro palladium(II) ([Pd(amphos)Cl2]), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine] palladium(O) (Pd(amphos)2), and allylpalladium(II) chloride dimer ([PdCl(C3H5)]2) and the like.

[0176] The term “suitable reducing agent” used in the present invention is selected from but not limited to Metal hydride such as not limited to LiAlH4, NaAlH4, NaBH4, KBH4, mixture of NaBH4& acetic acid, mixture of NaBFL & trifluoroacetic acid, mixture of NaBH4 & iodine, mixture of NaBFL & trimethylchlorosilane, mixture of NaBFL & magnesium chloride, mixture of NaBFL & calcium chloride, mixture of NaBFL & one of transition metal chlorides, mixture of NaBFL & BFs.etherate, sodium cyanoborohydride, sodium triacetoxy borohydride, aluminium hydride (AlH3), diisobutylaluminium hydride (DIBAL), Vitride {=Sodium bis(2-methoxyethoxy) aluminum hydride], Lithium tri-tert-butoxyaluminum hydride, Tributyltin hydride; boranes such as not limited to BH3-tetrahydrofuran, BH3-dimethyl sulfide; hydrazine; metal such as but not limited to Na, Fe, Ni, Zn, Sn in presence of acidic medium; Na-liquid ammonia; Silanes including but not limited to tri(C1-C6)alkylsilanes, tri(C1-C6)alkylsilyl halides; catalytic hydrogenation in presence of transition metals catalysts including but not limited to Ni, Pd, Pt, Rh, Re, Ru and Ir, including their oxides, hydroxides, acetates and combinations and the like; “enzymatic catalysts” selected from ketoreductase enzymes and the like; “chiral reducing agent” selected from butnot limited to Borane-DMS, Borane-THF and Borane-diethylaniline in presence of catalysts like (R)-2-Methyl-CBS-oxazaborolidine, (R)-2-phenyl-CBS-oxazaborolidine and (R)-2-butyl-CBS-oxazaborolidine; 9-BBN in combination with alpha-pinene; diisopinocamphenylborane; and B-chlorodiisopino camphenylborane (herein after referred as DIP chloride) and the like.

[0177] The term " suitable protecting group" as used herein the present invention is selected such that it is capable of protecting the oxygen atom. The “protecting group” is selected from, but not limited to "substituted or unsubstituted arylcarbonyl" such as benzoyl, p-methoxy benzoyl, p-phenyl benzoyl and the like; "straight chain or branched chain alkyl and alkenyl" such as tertiary butyl, allyl and the like; "substituted or unsubstituted acyl" such as acetyl, chloro acetyl, dichloro acetyl, trichloro acetyl, trifluoro acetyl, pivaloyl and the like; "substituted or unsubstituted arylalkyl" such as p-methoxy benzyl, p-nitrobenzyl, benzyl, p-bromo benzyl and the like; "(alkyl)m(aryl)3-msilyl" wherein, 'm' represents 0, 1, 2 and 3, such as trimethyl silyl, triethyl silyl, triisopropyl silyl, tributyl silyl, dimethylisopropyl silyl, diisopropyl silyl, tert-butyldimethyl silyl, tert-butyl diphenyl silyl and the like; "alkoxyalkyl" such as methoxymethyl, 2-methoxyethoxymethyl and the like; "aryloxy alkyl" such as benzyloxymethyl and the like; "substituted or unsubstituted tetrahydro-2H-pyran-2-yl"; "substituted or unsubstituted trityl" such as trityl, 4-methyltrityl and the like; "alkyl sulfonyl" such as methane sulfonyl, ethane sulfonyl and the like; "substituted or unsubstituted aryl sulfonyl" such as tosyl, nosyl and the like; protecting groups of the formula "-CO-O-R1" wherein R1represents C1-4alkyl or aryl or arylalkyl such as methoxy carbonyl, ethoxy carbonyl, benzyloxy carbonyl, 9-(fluorenylmethyloxy)carbonyl, tertiary butyloxy carbonyl and the like.

[0178] The term “suitable deprotecting agent” as used in the present invention may be selected based on the protecting group employed. The “deprotecting agent” may be selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate / imidazole, alkali metalbicarbonates, ammonia, aqueous ammonia, ammonium cerium(IV) nitrate; and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd / C, Pd(OH)2 / C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh / C, Ru, sodium borohydride, Na-liquid ammonia, Raney-Ni, Zn-acetic acid, tri(Ci-C6)alkylsilanes, tri(C1-C6)alkylsilyl halides and the like.

[0179] The term “pharmaceutically acceptable salts” or “salts” as used in the present invention is selected from but not limited to “inorganic acids” such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; “organic acids” such as acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; “alkali or alkaline earth metal salts” such as sodium, calcium, potassium and magnesium salts; “chiral acids” such as S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)- (+)-camphor sulfonic acid (lR)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)- bromocamphor- 10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine etc., and like.

[0180] In one embodiment, the present invention provides a process for the preparation of Obicetrapib of Formula I, the schematic description of the process is as shown in Scheme-I:

[0181]

[0182] wherein Pg = Protecting group; X= F, Cl, Br or I

[0183] Scheme-I

[0184] which comprises:

[0185] i. desalifying compound of Formula II,

[0186] salt

[0187]

[0188] Formula IIin the presence of a suitable base and a suitable solvent to provide a compound of Formula II’ (in-situ);

[0189]

[0190] Formula II'

[0191] ii. reacting the compound of Formula II’ (in-situ) with a compound of Formula III,

[0192]

[0193] Formula III

[0194] wherein X = Halogen

[0195] in the presence of a suitable solvent, optionally with a suitable base;

[0196] (OR)

[0197] desalifying compound of Formula IV’ with a suitable base in the presence of a suitable solvent;

[0198] • salt

[0199]

[0200] Formula IV

[0201] to provide a compound of Formula IV;

[0202]

[0203] Formula IV

[0204] iii. reductively aminating the compound of Formula IV with a compound of Formula V,

[0205]

[0206] Formula V

[0207] in the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,

[0208]

[0209] followed by reacting with a suitable reducing agent to provide a compound of Formula VII;

[0210]

[0211] iv. coupling the compound of Formula VII with a compound of Formula VIII,

[0212]

[0213] Formula VIII

[0214] wherein Pg = Protecting group; X = Halogen

[0215] in the presence of a suitable base, a suitable solvent and a suitable catalyst to provide a compound of Formula IX;

[0216]

[0217] wherein Pg = Protecting group

[0218] v. deprotecting the compound of Formula IX with a suitable deprotecting agent in the presence of a suitable solvent to provide a Obicetrapib of Formula I; vi. optionally, converting the Obicetrapib of Formula I to its pharmaceutically acceptable salts thereof; and

[0219] vii. optionally purifying Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0220] The starting compound of formula II is known in the art and are commercially available; the same may be prepared by the known methods or procured from the available commercial sources.

[0221] The step i) of the aforementioned process involves, desalification of compound of Formula II (the salt is other than methanesulfonic acid) which is carried out using a suitable base in the presence of a suitable solvent under appropriate reaction conditions to provide a compound of Formula II’ (in-situ). The suitable base used in the process is as defined above and preferably, inorganic base like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide; the suitable solvent used in the process is as defined above and preferably, polar solvent such as water. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 15 °C for sufficient period of time; preferably, about 15 mins to about 40 minutes; most preferably, about 20 mins to about 35 minutes.

[0222] The step ii) of the aforementioned process involves, reaction of a compound of Formula II’ (in-situ) with a compound of Formula III (wherein X is a Halogen such asF, Cl, Br or I; preferably, Cl) in the presence of a suitable solvent, optionally using a suitable base under appropriate reaction conditions to provide a compound of Formula IV. The suitable base used in the process is as defined above and preferably, organic base like triethylamine; the suitable solvent used in the process is as defined above and preferably, halogenated solvents such as dichloromethane, dichloroethane, chloroform, chlorobenzene, bromobenzene, carbon tetrachloride. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 15 °C for sufficient period of time; preferably, about 1 hour to about 3 hours; most preferably, about 1.5 hours to about 2.5 hours.

[0223] (OR)

[0224] Desalification of a compound of Formula IV’ with a suitable base in the presence of a suitable solvent under appropriate reaction conditions to provide a compound of Formula IV. The suitable base used in the process is as defined above and preferably, inorganic base like alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; the suitable solvent used in the process is as defined above and preferably, polar solvent such as water. The reaction is carried out at a suitable temperature of about 20 °C to about 35 °C; preferably, at about 25 °C to about 30 °C for sufficient period of time; preferably, about 2 hours to about 4 hours; most preferably, about 1.5 hours to about 2.5 hours.

[0225] The step iii) of the aforementioned process involves, reductive amination of compound of Formula IV with a compound of Formula V in the presence of a suitable solvent under appropriate reaction conditions to provide an imine compound of Formula VI, optionally isolating the imine compound of Formula VI, followed by reaction with a suitable reducing agent under appropriate reaction conditions to provide a compound of Formula VII. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, isobutanol; the suitable reducing agent used in the process is as defined above and preferably, NaBH₄ or mixture of Acetic acid and NaBH₄. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 0 °C to about 15°C for sufficient period of time; preferably, about 1 hour to about 3 hours; most preferably, about 1.5 hours to about 2.5 hours.

[0226] The step iv) of the aforementioned process involves, coupling reaction of a compound of Formula VII with a compound of Formula VIII in the presence of a suitable base, a suitable solvent and a suitable catalyst under appropriate reaction conditions to provide a compound of Formula IX. The suitable solvent used in the process is as defined above and preferably, nitrile solvent such as acetonitrile, propionitrile, isobutyronitrile; the suitable base used in the process is as defined above and preferably, inorganic base like alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate; the suitable catalyst used in the process is as defined above and preferably, palladium(II) acetate (Pd(OAc)2). The reaction is carried out at a suitable temperature of about 50 °C to about 90 °C; preferably, about 55 °C to about 75 °C for sufficient period of time; preferably, about 3 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0227] The step v) of the aforementioned process involves, deprotection of a compound of Formula IX with a suitable deprotecting agent in the presence of a suitable solvent under appropriate reaction conditions to provide Obicetrapib of Formula I. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol or acetic acid; most preferably acetic acid; the suitable deprotecting agent used in the process is as defined above and preferably, hydrochloric acid or aq. hydrochloric acid. The reaction is carried out at a suitable temperature of about 50 °C to about 90 °C; preferably, about 55 °C to about 75 °C for sufficient period of time; preferably, about 3 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0228] The step vi) of the aforementioned process involves, optional conversion of Obicetrapib of Formula I into its salts which may be carried out by treating Obicetrapib of Formula I with alkali or alkaline earth metal salts such as sodium, calcium, potassium and magnesium in a suitable solvent under appropriate reaction conditions to provide Obicetrapib salt; wherein the suitable solvent selected from alcoholicsolvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents, water and mixtures thereof; The reaction was carried out at a suitable temperature of about 20 °C to about 80 °C; preferably, at about 20 °C to about 60 °C for sufficient period of time; preferably, about 1 hour to about 24 hours.

[0229] The step vii) of the aforementioned process involves, optional purification of Obicetrapib and its pharmaceutically acceptable salts thereof may be carried out by using a suitable solvent or mixture of solvents or purification by recrystallizing or slurring in a suitable solvent or mixture of solvents under appropriate reaction conditions. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol. The Obicetrapib of formula I and its pharmaceutically acceptable salts further may be dried in a tray dryer, vacuum oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like or any other suitable dryer at a suitable temperature for a sufficient period of time with or without vacuum. The reaction is carried out at a suitable temperature of about 50 °C to about 90 °C; preferably, about 60 °C to about 80 °C for sufficient period of time; preferably, about 1 hour to 3 hours; most preferably, about 1.5 hours to about 2.5 hours.

[0230] In another embodiment, the present invention provides a process for the preparation of compound of Formula IV,

[0231]

[0232] Formula IV

[0233] which comprises:

[0234] i. desalifying compound of Formula II,

[0235]

[0236] Formula II

[0237] in the presence of a suitable base and a suitable solvent to provide a compound of Formula II’ (in-situ)

[0238]

[0239] Formula II'

[0240] ii. reacting the compound of Formula II' (in-situ) with a compound of Formula III,

[0241]

[0242] Formula III

[0243] ■wherein X = Halogen

[0244] in the presence of a suitable solvent, optionally with a suitable base, (OR)

[0245] desalifying compound of Formula IV’ with a suitable base in the presence of a suitable solvent,

[0246] to provide a compound of Formula IV; and

[0247] iii. converting the compound of Formula IV into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0248] The starting compound of formula IV’ is known in the art and are commercially available; the same may be prepared by the known methods or procured from the available commercial sources.

[0249] The steps i to ii) of the aforementioned process involves, process for the preparation of compound of Formula IV as described in steps i to ii) of the first embodiment.The step iii) of the aforementioned process involves converting the compound of Formula IV into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof as described in steps iii) to vii) of the first embodiment.

[0250] In another aspect, the present invention provides a process for the preparation of compound of Formula VII,

[0251]

[0252] which comprises:

[0253] i. reductively aminating the compound of Formula IV,

[0254]

[0255] Formula IV

[0256] with a compound of Formula V,

[0257]

[0258] Formula V

[0259] in the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,

[0260]

[0261] followed by reacting with a suitable reducing agent to provide a compound of Formula VII; and

[0262] ii. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0263] The starting compounds of formula IV & V are known in the art or may be prepared by the method described herein the present invention; the same may be prepared by the known methods or procured from the available commercial sources.

[0264] The step i) of the aforementioned process involves, process for the preparation of compound of Formula VII as described in step iii) of the first embodiment.

[0265] The step ii) of the aforementioned process involves, converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof as described in steps iv) to vii) of the first embodiment.

[0266] In another embodiment, the present invention provides a process for the preparation of compound of Formula IX,

[0267]

[0268] wherein Pg = Protecting group

[0269] which comprises:

[0270] i. coupling compound of Formula VII,

[0271]

[0272] with a compound of Formula VIII,

[0273]

[0274] Formula VIII

[0275] ■wherein Pg = Protecting group; X = Halogen

[0276] in the presence of a suitable base, a suitable solvent and a suitable catalyst to provide a compound of Formula IX; and

[0277] ii. converting the compound of Formula IX into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0278] The starting compound of formula VII & VIII are known in the art or may be prepared by the method described herein the present invention; the same may be prepared by the known methods or procured from the available commercial sources.

[0279] The step i) of the aforementioned process involves, process for the preparation of compound of Formula IX as described in step iv) of the first embodiment.

[0280] The step ii) of the aforementioned process involves, converting the compound of Formula IX into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof as described in steps v) to vii) of the first embodiment.

[0281] In another embodiment, the present invention provides a process for the preparation of Obicetrapib of Formula I, the schematic description of the process is as shown in Scheme-II:

[0282]

[0283] Formula I

[0284] Scheme-n

[0285] which comprises:

[0286] i. reacting compound of Formula X,

[0287]

[0288] Formula X

[0289] with a compound of Formula III,

[0290]

[0291] Formula III

[0292] ■wherein X - Halogen

[0293] in the presence of a suitable base and a suitable solvent to provide a compound of Formula XI;

[0294]

[0295] Formula XI

[0296] 11. reductively aminating the compound of Formula XI with a compound of Formula XII,

[0297]

[0298] Formula XII

[0299] in the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,

[0300]

[0301] followed by reacting with a suitable reducing agent to provide a compound of Formula VII; and

[0302]

[0303] iii. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0304] The starting compounds of formula X and III are known in the art and are commercially available; the same may be prepared by the known methods or procured from the available commercial sources.

[0305] The step i) of the aforementioned process involves, reaction of a compound of Formula X with a compound of Formula III (wherein X is a Halogen such as F, Cl, Br or I; preferably, Cl) in the presence of a suitable base and a suitable solvent under appropriate reaction conditions to provide a compound of Formula XI. The suitable base used in the process is as defined above and preferably, organic base like triethylamine; the suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 15 °C for sufficient period of time; preferably, about 2 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0306] The step ii) of the aforementioned process involves, reductive amination of a compound of Formula XI with a compound of Formula XII in the presence of a suitable solvent under appropriate reaction conditions to provide an imine compound of Formula VI, optional isolation of imine compound of Formula VI, followed by reacting with a suitable reducing agent to provide a compound of Formula VII. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol. The suitable reducing agent used in the process is as defined above and preferably, sodium cyanoborohydride. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 15 °C for sufficient period of time; preferably, about 2 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0307] The step iii) of the aforementioned process involves converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof as described in steps iv) to vii) of the first embodiment.

[0308] In another embodiment, the present invention provides a process for the preparation of Obicetrapib of Formula I, the schematic description of the process is as shown in Scheme-Ill:

[0309]

[0310] Formula I

[0311] Scheme-Ill

[0312] which comprises:

[0313] i. reacting compound of Formula X,

[0314]

[0315] Formula X

[0316] with a compound of Formula XII,

[0317]

[0318] Formula XII

[0319] in the presence of a suitable solvent to provide an imine compound of Formula XIII;

[0320]

[0321] ii. reacting compound of Formula XIII with a compound of Formula III,

[0322]

[0323] wherein X = Halogen

[0324] Formula IIIin the presence of a suitable base and a suitable solvent to provide a compound of Formula VI,

[0325]

[0326] iii. reducing compound of Formula VI with a suitable reducing agent in the presence of a suitable solvent to provide a compound of Formula VII; and iv. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

[0327] The starting compounds of formula X and XII are known in the art and are commercially available; the same may be prepared by the known methods or procured from the available commercial sources.

[0328] The step i) of the aforementioned process involves, reaction of a compound of Formula X with a compound of Formula XII in the presence of a suitable solvent under appropriate reaction conditions to provide an imine compound of Formula XIII. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol and ester solvents such as ethyl acetate, isopropyl acetate; most preferably, ethyl acetate and iso-propanol. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 15 °C for sufficient period of time; preferably, about 1 hour to about 3 hours; most preferably, about 1.5 hours to about 2.5 hours.

[0329] The step ii) of the aforementioned process involves, reaction of a compound of Formula XIII with a compound of Formula III (wherein X is a Halogen such as F, Cl, Br or I; preferably, Cl) in the presence of a suitable base and a suitable solvent under appropriate reaction conditions to provide a compound of Formula VI. The suitable base used in the process is as defined above and preferably, organic base like triethylamine; the suitable solvent used in the process is as defined above andpreferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, isobutanol. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 15 °C for sufficient period of time; preferably, about 3 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0330] The step iii) of the aforementioned process involves, reduction of a compound of Formula VI with a suitable reducing agent in the presence of a suitable solvent under appropriate reaction conditions to provide a compound of Formula VII. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol. The suitable reducing agent used in the process is as defined above and preferably, sodium triacetoxyborohydride. The reaction is carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 15 °C for sufficient period of time; preferably, about 3 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0331] The step iv) of the aforementioned process involves, conversion of a compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof as described in steps iv) to vii) of the first embodiment.

[0332] In another embodiment, the present invention provides a process for the preparation of Obicetrapib sodium of Formula IA,

[0333]

[0334] which comprises:

[0335] i. dissolving crude Obicetrapib of Formula I in a suitable solvent or mixture of solvents at a suitable temperature;

[0336] ii. adding sodium source to the step i) solution at a suitable temperature;iii. isolating Obicetrapib sodium of Formula IA.

[0337] The starting crude Obicetrapib of Formula I is known in the art or may be prepared by the method described herein the present invention.

[0338] The steps i) of the aforementioned process involves, dissolution of crude Obicetrapib of Formula I in a suitable solvent or a mixture of a solvents at a suitable temperature i.e., less than 35°C followed by activated carbon was added under appropriate reaction conditions. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol; most preferably, ethanol.

[0339] The steps ii) of the aforementioned process involves, addition of sodium source to the step i) solution at a suitable temperature under appropriate reaction conditions to provide Obicetrapib sodium of Formula IA. The suitable sodium source used in the process is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate; preferably, sodium hydroxide. The reaction is carried out at a suitable temperature of about 20 °C to about 35 °C; preferably, about 25 °C to about 35 °C for sufficient period of time; preferably, about 3 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0340] The step iii) of the aforementioned process involves, isolation of Obicetrapib sodium of Formula IA may be carried out by the methods known in the art; for example, cooling the reaction mass temperature to less than 35°C, maintaining for sufficient period of time till complete formation of material, preferably about 1.5 hours to about 2.5 hours followed by filtration.

[0341] In another aspect, the present invention provides an amorphous form of Obicetrapib sodium of Formula IA,

[0342]

[0343] In another aspect, the present invention provides a process for the preparation of Obicetrapib hemicalcium of Formula I’,

[0344]

[0345] Formula I'

[0346] which comprises:

[0347] iii. treating amorphous form of Obicetrapib sodium of Formula IA,

[0348]

[0349] with a suitable calcium source in a suitable solvent or mixture of solvents at a suitable temperature;

[0350] iv. isolating pure Obicetrapib hemicalcium of Formula I’.The starting Obicetrapib sodium of Formula IA is known in the art or may be prepared by the method described herein the present invention.

[0351] The steps i) of the aforementioned process involves, treating of Obicetrapib sodium of Formula IA with a suitable calcium source in a suitable solvent or mixture of solvents at a suitable temperature under appropriate reaction conditions to obtain Obicetrapib hemicalcium of Formula I’. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, isobutanol and ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate; most preferably, ethanol and ethyl acetate. The suitable calcium source used in the process is selected from but not limited to Calcium carbonate, Calcium phosphate, Calcium hydroxide, Calcium chloride, Calcium sulfate; preferably, Calcium chloride. The reaction was carried out at a suitable temperature of about 0 °C to about 20 °C; preferably, about 5 °C to about 10 °C for sufficient period of time; preferably, about 3 hours to about 5 hours; most preferably, about 3.5 hours to about 4.5 hours.

[0352] The step ii) of the aforementioned process involves, isolation of Obicetrapib hemicalcium of Formula I’ may be carried out by the methods known in the art; for example, cooling the reaction mass temperature to less than 35°C, maintaining for sufficient period of time till complete formation of material, preferably about 1.5 hours to about 2.5 hours followed by filtration.

[0353] In another embodiment, the present invention provides a process for the purification of Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof, which comprises:

[0354] i. dissolving crude Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof in a suitable solvent or a mixture of a suitable solvents at a suitable temperature;

[0355] ii. heating the step i) solution at a suitable temperature; and

[0356] iii. isolating the pure Obicetrapib of Formula I or its pharmaceutically acceptable salts thereof.The starting crude Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof is known in the art or may be prepared by the method described herein the present invention.

[0357] The steps i) of the aforementioned process involves, dissolution of crude Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof in a suitable solvent or a mixture of a solvents at a suitable temperature i.e., less than 35°C followed by activated carbon was added under appropriate reaction conditions. The suitable solvent used in the process is as defined above and preferably, alcohol solvent such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol.

[0358] The steps ii) of the aforementioned process involves the reaction mass is carried out at a suitable temperature of about 50 °C to about 100 °C; preferably, about 60 °C to about 80 °C for sufficient period of time; preferably, about 1 hour to about 3 hours; most preferably, about 1.5 hours to about 2.5 hours.

[0359] The step iii) of the aforementioned process involves, isolation of Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof may be carried out by the methods known in the art; for example, cooling the reaction mass temperature to less than 35°C, maintaining for sufficient period of time till complete formation of material, preferably about 1.5 hours to about 2.5 hours followed by filtration.

[0360] In another embodiment, the present invention provides a process for the preparation of Obicetrapib or its sodium / calcium salt obtained in the processes are having free of below impurities:

[0361]

[0362] In an embodiment, the content of above impurities either in Obicetrapib, or its sodium / calcium salt individually is having about 0.0001 to 0.10% by HPLC analysis. More specifically, the content of each individual impurity is below 0.05% by HPLC analysis.

[0363] The impurity profile of Obicetrapib of Formula I and Obicetrapib hemicalcium of Formula I’ obtained in the present invention complies with the ICH guidelines in terms of HPLC purity.

[0364] In an embodiment, the Obicetrapib of Formula I and Obicetrapib hemicalcium of Formula I’ may further be dried by adopting suitable drying techniques such as tray dryer, vacuum oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like or any other suitable dryer at a suitable temperature for a sufficient period of time with or without vacuum.

[0365] Accordingly, in a further embodiment, there is provided a pharmaceutical composition comprising the pure Obicetrapib of Formula I and Obicetrapib hemicalcium ofFormula I’ of the present invention, one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients.

[0366] Pharmaceutical compositions comprising the pure Obicetrapib of Formula I and Obicetrapib hemicalcium of Formula I’ of the present invention may be administered orally, topically, parenterally, by inhalation or spray, rectally, or in the form of injectables.

[0367] EXPERIMENTAL PORTION:

[0368] The details of the invention are given in the examples provided below, which are given to illustrate the invention only and, therefore, should not be construed to limit the scope of the invention.

[0369] Example 1: Process for the preparation of [2R,4S]4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester (Formula IV).

[0370] Method-1: To a clean and dry RBF, (2R,4S)-2-ethyl-6-(trifluoromethyl)-l, 2,3,4-tetrahydroquinolin-4-amine mesylate (10.0 grams; 1.0 equivalent) in water (100.0 mL; 10.0 volumes) and NaOH solution (20 mL; 2.0 volumes) were added at 25 °C to 35 °C. Cool the reaction mass to 5 °C to 10 °C and the mixture was stirred for 20 to 30 minutes at the same temperature. Ethyl acetate (100.0 mL; 10.0 volumes) was added to the reaction mixture and stirred for 20 to 30 minutes 5 °C to 10 °C. The organic and aqueous layers were separated from the filtrate; the aqueous layer was washed with ethyl acetate (100.0 mL; 10.0 volumes). The organic layers were combined and distilled off under vacuum at below 45°C. Methylene dichloride (100.0 mL; 10.0 volumes) and triethylamine (4.9 mL; 1.2 equivalent) were added at 5 °C to 10 °C and the mixture was stirred for 1 to 2 hours hour at the same temperature followed by ethyl chloroformate (3.814 grams; 1.2 equivalents) was added slowly to the reaction mass and stirred for 2 to 3 hours at the same temperature. After completion of the reaction, water (100.0 mL; 10.0 volumes) was added to the reaction mass. The organic and aqueous layers were separated, the aqueous layer was washed with Methylene dichloride (100.0 mL; 10.0 volumes). The organic layers were combined and distilledoff under vacuum at below 45°C. The obtained compound was purified by flash column chromatography to get the title compound. Yield: 6.97 grams (75.0 %).

[0371] Method-2: To a stirred solution of ethyl (2R,4S)-4-amino-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-l(2H)-carboxylate hydrochloride (10.0 grams; 1.0 equivalent) in water (100.0 mL; 10.0 volumes) at 25 °C to 35 °C. NaHCO3 (3.6 grams; 1.5 equivalent) was added to the above solution in lot wise and stirred for 2 hours at the same temperature. Finally, filtered the solid and washed with water (50.0 mL, 5.0 volumes) and dried to get the title compound. Yield: 7.6 grams (85.0 %).

[0372] Example 2: Process for the preparation of (R, E)-4-((3,5-bis(trifluoromethyl)benzyl)imino)-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-l(2H) -carboxylate (Formula VI):

[0373] To a clean and dry RBF, (R, E)-N-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(lH)-imine (14.0 grams; 1.0 equivalent) in methanol (140.0 mL; 10.0 volumes) was added at 25 to 35°C. The reaction mass was cooled to 5 to 10 °C, then triethylamine (4.99 mL; 1.2 equivalents) and ethyl chloroformate (3.88 grams; 1.2 equivalents) were added and stirred for 4 to 5 hours at the same temperature. After completion of the reaction, water (140.0 mL; 10.0 volumes) and ethyl acetate (140.0 mL; 10.0 volumes) were added to the reaction mass. The organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate (70.0 mL; 5 volumes). The organic layers were combined and distilled off under vacuum at below 45°C. The obtained compound was purified by flash column chromatography to get the title compound. Yield: 11.61 grams (72.0 %).

[0374] Example 3: Process for the preparation of [2R,4S]4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester (Formula VII):

[0375] Method-1: To a clean and dry RBF, [2R,4S]4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester (6.5 grams; 1.0 equivalent) in methanol (45.5 mL; 7.0 volumes), 3,5-bis(trifluoromethyl)benzaldehyde (5.97 grams; 1.2 equivalents), and acetic acid (0.06 grams; 0.05 equivalent) were added at 25 °C to35 °C. Cool the reaction mass to 0 °C to 10 °C and the mixture was stirred for 20 to 30 minutes at the same temperature. Sodium borohydride (0.39 grams; 0.5 equivalent) in lot wise was added to the reaction mass and stirred for 2 to 3 hours at the same temperature. After completion of the reaction, water (65.0 mL; 10.0 volumes) and methylene dichloride (65.0 mL; 10.0 volumes) were added to the reaction mass. The organic and aqueous layers were separated and distilled off the organic layer under vacuum at below 45°C to get the title compound. Yield: 8.9 grams (80.0 %).

[0376] Method-2: To a clean and dry RBF, ethyl (R)-2-ethyl-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinoline-l(2H)-carboxylate (9.5 grams; 1.0 equivalent) in methanol (95.0 mL; 10.0 volumes) was added at 25 to 35°C. The reaction mass was cooled to 5 to 10 °C, 3,5-bis(trifluoromethyl)benzylamine (8.79 grams; 1.2 equivalents), acetic acid (0.09 grams; 0.05 equivalents) and sodium cyanoborohydride (1.89 grams; 1.0 equivalents) in lot wise were added and stirred for 4 to 5 hours at the same temperature. After completion of the reaction, water (95.0 mL; 10.0 volumes) and ethyl acetate (95.0 mL; 10.0 volumes) were added to the reaction mass. The organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate (95.0 mL; 10.0 volumes). The organic layers were combined and distilled off under vacuum at below 45 °C. The obtained compound was purified by flash column chromatography to get the title compound. Yield: 12.41 grams (76.0 %).

[0377] Method-3: To a clean and dry RBF, ethyl (R, E)-4-((3,5-bis(trifluoromethyl)benzyl)imino)-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-l(2H)-carboxylate (12.0 grams, 1.0 equivalent) in methanol (60.0 mL; 5.0 volumes) was added at 25 to 35°C. The reaction mass was cooled to 5 to 10 °C, sodium triacetoxyborohydride (2.35 grams; 0.5 equivalents) in lot wise was added and stirred for 4 to 5 hours at the same temperature. After completion of the reaction, water (120.0 mL; 10.0 volumes) and ethyl acetate (120.0 mL; 10.0 volumes) were added to the reaction mass. The organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate (60.0 mL; 5 volumes). The organic layers were combined and distilled off under vacuum at below 45°C. The obtained compound was purifiedby flash column chromatography to get the title compound. Yield: 8.46 grams (70.0 %).

[0378] Example 4: Process for the preparation of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tertbutoxycarbonyl-propoxy)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester (Formula IX):

[0379] To a clean and dry RBF, [2R,4S]4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester (8.0 grams, 1.0 equivalent) in acetonitrile (56.0 mL; 7.0 volumes) and potassium carbonate (3.15 grams; 1.5 equivalent) were added at 25 to 35 °C under argon atmosphere. Pd(OAc)2(0.17 grams; 0.05 equivalent) and tert-butyl 4-((2-chloropyrimidin-5-yl)oxy)butanoate (4.0 grams; 1.0 equivalent) were added to the reaction mass. The reaction mass was heated to 60 to 70 °C and stirred for 3.5 to 4.5 hours at the same temperature. After completion of the reaction, water (80.0 mL; 10.0 volumes) and ethyl acetate (80.0 mL; 10.0 volumes) were added to the reaction mass. The organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate (80.0 mL; 10.0 volumes). The organic layers were combined and distilled off under vacuum at below 45°C. The obtained compound was purified by flash column chromatography to get the title compound. Yield: 9.97 grams (87.0 %).

[0380] Example 5: Process for the preparation of ethyl (R)-2-ethyl-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinoline-l(2H)-carboxylate (Formula XI):

[0381] To a clean and dry RBF, (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(lH)-one (10.0 grams; 1.0 equivalent) in methanol (70.0 mL; 7.0 volumes) was added at 25 to 35 °C. The reaction mass was cooled to 5 to 10 °C, triethylamine (8.59 mL; 1.5 equivalents) and ethyl chloroformate (5.35 grams; 1.2 equivalents) were added and stirred for 4 to 5 hours at the same temperature. After completion of the reaction, water (70.0 mL; 10.0 volumes) and ethyl acetate (70.0 mL; 10.0 volumes) were added to the reaction mass. The organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate (7.0 mL; 10.0 volumes). The organic layers were combined and distilled off under vacuum at below 45°C. The obtained compound was purifiedby flash column chromatography to get the title compound. Yield: 10.21 grams (79.0 %).

[0382] Example 6: Process for the preparation of (R, E)-N-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(lH)-imine (Formula XIII):

[0383] To a clean and dry RBF, (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(lH)-one (10.0 grams; 1.0 equivalent) in ethyl acetate (50.0 mL; 5.0 volumes) and isopropyl alcohol (50.0 mL; 5.0 volumes) was added at 25 to 35°C. The reaction mass was cooled to 5 to 10 °C, then 3,5-bis(trifluoromethyl)benzylamine (11.99 grams; 1.2 equivalents) and acetic acid (0.12 grams; 0.05 equivalents) were added and stirred for 1 to 2 hours at the same temperature. After completion of the reaction, water (100.0 mL; 10.0 volumes) was added to the reaction mass. The organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate (25.0 mL; 2.5 volumes) and isopropyl alcohol (25.0 mL; 2.5 volumes). The organic layers were combined and distilled off under vacuum at below 45°C to get the title compound. Yield: 14.82 grams (77.0 %).

[0384] Example 7: Process for the preparation of Obicetrapib of Formula I:

[0385] To a clean and dry RBF, (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tertbutoxycarbonyl-propoxy)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester (8.5 grams; 1.0 equivalent) in Acetic acid (42.5 mL, 5.0 mL) and aqueous HC1 solution (42.5 mL; 5.0 volumes) were added at 25 to 35 °C. The reaction mass was heated to 60 to 70 °C and stirred for 3.5 to 4.5 hours at the same temperature. After completion of the reaction, the reaction mass was distilled off under vacuum at below 65°C. Ethyl acetate (850 mL; 10.0 volumes) was added and stirred for 20 to 30 minutes. The organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate (850.0 mL; 10.0 volumes). The organic layers were combined and distilled off under vacuum at below 45 °C. The obtained compound was purified by flash column chromatography to get the title compound. Yield: 5.9 grams (75.0 %).Example 8: Process for the purification of Obicetrapib of Formula I:

[0386] To a stirred solution of crude Obicetrapib of Formula I (5.5 grams; 1.0 equivalent) in ethanol (59.0 mL; 10.0 volumes) and activated carbon (10.0 mol%) was added at 25 to 35 °C. The reaction mass was heated to 65 to 75°C and stirred for 20 to 30 minutes at the same temperature. Then the reaction mass was cooled to 5 to 10 °C and stirred for 2 to 3 hours at the same temperature. Finally, filtered the solid and washed with ethanol (27.5.0 mL, 5.0 volumes) and dried to get the title compound. Yield: 4.98 grams (75.0 %).

[0387] Example 9: Process for the preparation of Obicetrapib sodium of Formula IA:

[0388] To a stirred solution of Obicetrapib (5.0 grams; 1.0 equivalent) in ethanol (50.0 mL; 10.0 volumes) and activated carbon (10.0 mol%) were added at 25 to 35 °C. NaOH (0.3 grams; 1.1 equivalent) solution was added at 25-35°C and stirred for 4 hours at the same temperature. Distilled off the solvents under vacuum at below 45°C to 50°C. toluene (50.0 mL; 10.0 volumes) and n-Heptane (50.0 mL; 10.0 volumes) were added at 25 to 35 °C and stirred for 2 hours at the same temperature. Finally, filtered the solid and washed with n-Heptane (50.0 mL; 10.0 volumes) and dried to get the title compound. Yield: 4.38 grams (85.0 %).

[0389] Example 10: Process for the preparation of Obicetrapib hemicalcium of Formula I’:

[0390] To a stirred solution of Obicetrapib sodium (1.0 grams; 1.0 equivalent) in ethanol (10.0 mL; 10.0 volumes) at 25 to 35 °C. CaCl2 (0.52 grams; 3.5 equivalent) in water (20.0 mL; 20.0 volumes) and ethyl acetate (0.5 mL; 0.5 volumes) were added to the above solution at 5 °C to 10 °C and stirred for 4 hours at the same temperature. Finally, filtered the solid and washed with water (10.0 mL; 10.0 volumes) and n-Heptane (10.0 mL; 10.0 volumes) and dried to get the title compound. Yield: 0.75 grams (75.0 %).

Claims

We claim:

1. A process for the preparation of Obicetrapib of Formula I,which comprises:i. desalifying compound of Formula II,Formula IIin the presence of a suitable base and a suitable solvent to provide a compound of Formula II’ (in-situ);Formula II'ii. reacting the compound of Formula II’ (in-situ) with a compound of Formula III,Formula III•wherein X = Halogenin the presence of a suitable solvent, optionally with a suitable base,(OR)desalifying compound of Formula IV’ with a suitable base in the presence of a suitable solvent,• saltFormula IV'to provide a compound of Formula IV;Formula IViii. reductively aminating the compound of Formula IV with a compound of Formula V,Formula Vin the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,followed by reacting with a suitable reducing agent to provide a compound of Formula VII;iv. coupling the compound of Formula VII with a compound of Formula VIII,Formula VIIIwherein Pg = Protecting group; X = Halogenin the presence of a suitable base, a suitable solvent and a suitable catalyst to provide a compound of Formula IX,wherein Pg = Protecting groupv. deprotecting the compound of Formula IX with a suitable deprotecting agent in the presence of a suitable solvent to provide a Obicetrapib of Formula I; vi. optionally, converting the Obicetrapib of Formula I to its pharmaceutically acceptable salts thereof; andvii. optionally purifying Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

2. The process as claimed in claim 1, wherein in the deprotecting agent is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate / imidazole, alkali metal bicarbonates, ammonia, aqueous ammonia, ammonium cerium (IV) nitrate; and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd / C, Pd(OH)2 / C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh / C, Ru, sodium borohydride, Na-liquid ammonia, Raney-Ni, Zn-acetic acid, tri(Ci-C6)alkylsilanes, tri(C1-C6)alkylsilyl halides and the like.

3. A process for the preparation of compound of Formula IV,Formula IVwhich comprises:i. desalifying compound of Formula II,Formula IIin the presence of a suitable base and a suitable solvent to provide a compound of Formula II’ (in-situ);Formula IPii. reacting the compound of Formula II’ (in-situ) with a compound of Formula III,Formula III-wherein X = Halogenin the presence of a suitable solvent, optionally with a suitable base, (OR)desalifying compound of Formula IV’ with a suitable base in the presence of a suitable solvent,• saltFormula IV'to provide a compound of Formula IV; andiii. converting the compound of Formula IV into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

4. A process for the preparation of compound of Formula VII,Formula VIIwhich comprises:i. reductively aminating the compound of Formula IV,with a compound of Formula V,Formula Vin the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,followed by reacting with a suitable reducing agent to provide a compound of Formula VII;ii. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

5. A process for the preparation of compound of Formula IX,wherein Pg = Protecting groupwhich comprises:i. coupling compound of Formula VII,with a compound of Formula VIII,Formula VIIIwherein Pg = Protecting group; X = Halogenin the presence of a suitable base, a suitable solvent and a suitable catalyst to provide a compound of Formula IX; andii. converting the compound of Formula IX into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

6. The process as claimed in claims 1 & 5, wherein in the catalyst is selected from [l,l'-bis(diphenylphosphino) ferrocene] dichloro palladium (II) ([Pd(dppf)Cl2]), [l,l'-bis(di-tert-butylphoshino) ferrocene] dichloro palladium(I) ([Pd(dtbpf)Cl2]) tetrakis (triphenyl phosphine) palladium(O) (Pd(PPh3)4), bromo(tri-tert- butylphosphine) palladium(I) dimer ([Pd(p-Br)(t-Bu3P)]2), bis(tri-tert- butylphosphine)palladium(O) ([Pd(tBu3P)2]), palladium(II) acetate (Pd(OAc)2), palladium(II) chloride (PdCh), bis (benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Cl2]), bis(triphenylphosphine) palladium(II) dichloride ([Pd(PPh3)2Ch]), bis (acetonitrile)palladium(II) dichloride ([Pd(NCMe)2C12]), bis[di-tert-butyl(4-dimethyl aminophenyl)phosphine] dichloro palladium(II) ( [Pd(ampho s )Ch] ), bis [di-tert-buty 1(4 -dimethylaminophenyl )pho sphine] palladium(O) (Pd(amphos)2), and allylpalladium(II) chloride dimer ([PdCl(C3H5)]2).

7. A process for the preparation of compound of Formula VII,which comprises:reacting compound of Formula X,with a compound of Formula III,Formula III•wherein X = Halogenin the presence of a suitable base and a suitable solvent to provide a compound of Formula XI,Formula XIii. reductively aminating the compound of Formula XI with a compound of Formula XII,Formula XIIin the presence of a suitable solvent to provide an imine compound of Formula VI, optionally isolating the compound of Formula VI,followed by reacting with a suitable reducing agent to provide a compound of Formula VII; andiii. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

8. A process for the preparation of compound of Formula VII,which comprises:i. reacting compound of Formula X,Formula Xwith a compound of Formula XII,Formula XIIin the presence of a suitable solvent to provide an imine compound of Formula XIII,reacting compound of Formula XIII with a compound of Formula III,Formula III•wherein X = Halogenin the presence of a suitable base and a suitable solvent to provide a compound of Formula VI,Formula VIiii. reducing compound of Formula VI with a suitable reducing agent in the presence of a suitable solvent to provide a compound of Formula VII; and iv. converting the compound of Formula VII into Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

9. The process as claimed in claims 1, 4, 7 to 8, wherein in the reducing agent is selected from Metal hydride such as not limited to LiAIFU, NaAlIU, NaBFU, KBH4, mixture of NaBFU & acetic acid, mixture of NaBFU & trifluoro acetic acid, mixture of NaBFU & iodine, mixture of NaBFU & trimethylchlorosilane, mixture of NaBFU & magnesium chloride, mixture of NaBFU & calcium chloride, mixture of NaBFU & one of transition metal chlorides, mixture of NaBFU & BF3. etherate, sodium cyanoborohydride, sodium triacetoxy borohydride, aluminium hydride (AlH3), diisobutylaluminium hydride (DIB AU), Vitride {=Sodium bis(2- methoxyethoxy) aluminum hydride}, Uithium tri-tert-butoxyaluminum hydride, Tributyltin hydride; boranes such as not limited to BFU-tetrahydrofuran, BH3- dimethyl sulfide; hydrazine; metal such as but not limited to Na, Fe, Ni, Zn, Sn in presence of acidic medium; Na-liquid ammonia; Silanes including but not limited to tri(C1-C6)alkylsilanes, tri(C1-C6)alkylsilyl halides; catalytic hydrogenation in presence of transition metals catalysts including but not limited to Ni, Pd, Pt, Rh,Re, Ru and Ir, including their oxides, hydroxides, acetates and combinations and the like; “enzymatic catalysts” selected from ketoreductase enzymes and the like; “chiral reducing agent” selected from but not limited to Borane-DMS, Borane- THF and Borane-diethylaniline in presence of catalysts like (R)-2- Methyl-CBS-oxazaborolidine, (R)-2-phenyl-CBS-oxazaborolidine and (R)- 2-butyl-CBS-oxazaborolidine; 9-BBN in combination with alpha-pinene; diisopinocamphenylborane; and B-chlorodiisopino camphenylborane (herein after referred as DIP chloride).

10. A process for the preparation of Obicetrapib sodium of Formula IA,which comprises:i. dissolving crude Obicetrapib of Formula I in a suitable solvent or mixture of solvents at a suitable temperature;ii. adding sodium source to the step i) solution at a suitable temperature;iii. isolating Obicetrapib sodium of Formula IA.

11. The process as claimed in claim 10, wherein the sodium source is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate or mixtures thereof.

12. An amorphous form of Obicetrapib sodium of Formula IA,13. A process for the preparation of Obicetrapib hemicalcium of Formula I’,Formula I'which comprises:i. treating amorphous form of Obicetrapib sodium of Formula IA,with a suitable calcium source in a suitable solvent or mixture of solvents at a suitable temperature;ii. isolating pure Obicetrapib hemicalcium of Formula I’.

14. The process as claimed in claim 13, wherein the calcium source is selected from Calcium carbonate, Calcium phosphate, Calcium hydroxide, Calcium chloride, Calcium sulfate or mixtures thereof.

15. A process for the purification of Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof, which comprises:i. dissolving crude Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof in a suitable solvent or a mixture of a suitable solvents at a suitable temperature;ii. heating the step i) solution at a suitable temperature; andiii. isolating the pure Obicetrapib of Formula I and its pharmaceutically acceptable salts thereof.

16. The process as claimed in claims 1 to 15, wherein in the base is selected from inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, ammonia or organic bases such as triethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), lithiumdiisopropyl-amine (LDA), n-butyl lithium, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMM), piperidine, dimethyl amino pyridine (DMAP), morpholine, pyridine, 2,6- lutidine, 1,4-diazabicyclo [2.2.2]octane (DABCO), cesium fluoride, cesium carbonate, potassium phosphate (tripotassium phosphate), potassium hydrogen phosphate, hydrates of potassium phosphate or mixtures thereof.

17. The process as claimed in claims 1 to 15, wherein the solvent or mixture of solvents are selected from alcohol solvents, ester solvents, ether solvents, ketone solvents, halogenated solvents, hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide, polar solvents, formic acid, acetic acid or mixtures thereof.

18. The process as claimed in any of the proceeding claims, wherein the purity by HPLC of Obicetrapib and Obicetrapib hemicalcium are having more than 98%, preferably more than 99% and most preferably 99.5% and above.

19. The Obicetrapib or its sodium / calcium salt obtained in the processes of proceeding claims is having free of below impurities:

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