WO2019043724A1 - Procédés pour la préparation de l'acide (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tétrahydroisoquinoléine-6-carboxamido)-3-(3-(méthylsulfonyl)phényl)propanoïque et de polymorphes de celui-ci - Google Patents

Procédés pour la préparation de l'acide (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tétrahydroisoquinoléine-6-carboxamido)-3-(3-(méthylsulfonyl)phényl)propanoïque et de polymorphes de celui-ci Download PDF

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WO2019043724A1
WO2019043724A1 PCT/IN2018/050552 IN2018050552W WO2019043724A1 WO 2019043724 A1 WO2019043724 A1 WO 2019043724A1 IN 2018050552 W IN2018050552 W IN 2018050552W WO 2019043724 A1 WO2019043724 A1 WO 2019043724A1
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formula
compound
solvents
acid
reaction mixture
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PCT/IN2018/050552
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Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Venkat Reddy Ghojala
Rajeshwar Reddy Sagyam
Srinivasulu Rangineni
Rajashekar Kommera
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Msn Laboratories Private Limited, R&D Center
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention provides processes for the preparation of (S)-2-(2-(benzofuran- 6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methyl sulfonyl)phenyl)propanoic acid represented by the following structural formula- 1 and polymorphs thereof.
  • US8080562B2 (herein after referred as US'562 patent) discloses a process for the synthesis of Lifitegrast and its various intermediate compounds in scheme-3 & scheme-5 which is shown below.
  • US8367701B2 describes five crystalline polymorphic forms of Lifitegrast namely form- A, form-B, form-C, form-D, form-E and amorphous form.
  • WO2014018748 describes crystalline form -II of Lifitegrast and process for its preparation.
  • IPCOM000250248D describes a crystalline polymorph of Lifitegrast and process for its preparation.
  • IPCOM000250498D discloses three crystalline forms of Lifitegrast namely form-i, form-ii, form-iii and processes for their preparation. Since the development of new polymorphic forms of an active pharmaceutical ingredient provides new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic forms is always encouraged.
  • solid state study of an active pharmaceutical ingredient aims to widen the variety of crystalline forms that a formulation scientist has available for designing a pharmaceutical dosage form with desired characteristics.
  • the first aspect of the present invention is to provide a process for the preparation of (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid compound of formula-1.
  • the second aspect of the present invention is to provide an improved process for the preparation of compound of formula-1.
  • the third aspect of the present invention is to provide a novel crystalline polymorph of compound of formula-1, herein after designated as form-M.
  • the fourth aspect of the present invention is to provide a novel crystalline polymorph of compound of formula-1, herein after designated as form-S.
  • the fifth aspect of the present invention is to provide a novel crystalline polymorph of compound of formula-1, herein after designated as crystalline form-N.
  • the sixth aspect of the present invention is to provide a novel crystalline polymorph of compound of formula-1, herein after designated as crystalline form-L.
  • the seventh aspect of the present invention is to provide a process for the preparation of compound of formula-1.
  • the eighth aspect of the present invention is to provide a novel process for the preparation of compound of formula-1.
  • the ninth aspect of the present invention is to provide alternate process for the preparation of compound of formula- 1.
  • the tenth aspect of the present invention is to provide a novel process for the preparation of compound of formula- 1.
  • the eleventh aspect of the present invention is to provide another novel process for the preparation of compound of formula- 1.
  • the twelfth aspect of the present invention is to provide another process for the preparation of compound of formula- 1.
  • the thirteenth aspect of the present invention is to provide a novel process for the preparation of compound of formula- 1.
  • Figure- 1 Illustrates powder X-Ray diffraction (PXRD) pattern of compound of formula-5
  • Figure-2 Illustrates the PXRD pattern of crystalline form-M of compound of formula- 1
  • Figure-3 Illustrates the PXRD pattern of crystalline form-S of compound of formula- 1
  • Figure-4 Illustrates the PXRD pattern of crystalline form-N of compound of formula- 1 obtained according to example-5
  • Figure-5 Illustrates the PXRD pattern of crystalline polymorph of compound of formula- 1 obtained according to example-6
  • Figure-6 Illustrates the PXRD pattern of compound of formula- 1 obtained according to example- 13
  • Figure-7 Illustrates the PXRD pattern of crystalline form-L of compound of formula- 1
  • Figure-8 Illustrates the PXRD pattern of compound of formula- 1 obtained after drying the crystalline form-L at 100°C for 10 hr
  • suitable solvent used in the present invention can be selected from but not limited to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene 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; "ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethyls
  • the “suitable base” used in the present invention can be selected from but not limited 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, cesium hydroxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; ammonia; “organic bases” like “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium
  • suitable acid used in the present invention can be selected from but not limited to "inorganic acids” such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acids” such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid
  • the "suitable coupling agent" used in the present invention can be selected from but not limited to ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), ⁇ , ⁇ ' -carbonyl diimidazole (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-tetramethyluronium hexafluorophosphate (HBTU), lH-benzotriazolium l-[bis(dimethylamino)methylene]-5- chloro-hexafluor
  • the suitable "amine protecting group” or “N-protecting group” 'PG' can be selected from but not limited to alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p- methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), tnfluoroacetyl (TFA), trichloroethoxycarbonyl (Troc), pivaloyl (Piv), triphenylmethyl (trityl or Tr
  • the suitable amine protecting agent can be selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.
  • Suitable amine protecting agent can be selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (Fmoc chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, alkyl haloformates such as methyl chloroformate, ethyl chloroformate, isopropyl chloroformate and the like, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, tnfluoroacetyl chloride, trichloroethoxycarbonyl chloride, pivaloyl chloride, triphenylmethyl chloride (tr
  • the "suitable deprotecting agent” can be selected based on the protecting group employed.
  • the “suitable deprotecting agent” can 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 metal bicarbonates, ammonia, aqueous ammonia, ammonium cerium(IV) nitrate (CAN); 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, sodium
  • 'X' represents halogen such as F, CI, Br & I.
  • the first aspect of the present invention provides a process for the preparation of (S)- 2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3- (3-(methylsulfonyl)phenyl)propanoic acid compound of formula- 1, comprising;
  • R 2 ' represents substituted or unsubstituted aryl and the substituents wherever used can be independently selected from halogens such as F, CI, Br & I, ⁇ 0 2 and the substitution can be takes place at single or multiple positions on aryl group;
  • step-a) & step-c) the suitable coupling agent is selected from the coupling agents as described above;
  • step-a), step-b) & step-c) the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or mixtures thereof;
  • step-a) to step-c) the suitable solvent wherever necessary is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof.
  • the compound of formula-3 can be optionally isolated from the reaction mixture as a solid and purified from a suitable solvent or mixture of solvents as defined above to provide pure compound of formula-3.
  • the activated compounds which are formed by reacting compound of formula-2 or compound of formula-5 with suitable coupling agent optionally in presence of a suitable base in a suitable solvent can optionally be isolated from the reaction mixture in solid form and can be further purified from a suitable solvent or mixture of solvents. Then the said activated compounds can be further reacted with compound of formula R 2 -OH (in case of compound of formula-2) or compound of formula-6 or its salt (in case of compound of formula-5) in a suitable solvent optionally in presence of a suitable base to provide compound of formula-3 or compound of formula- 1 respectively.
  • the said activated compounds are not isolated from the reaction mixture and are reacted in-situ with the subsequent compounds to provide the corresponding products.
  • a preferred embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising;
  • step-a) reacting compound of formula-5 a with compound of formula-6 or its salt in a suitable solvent optionally in presence of a suitable base to provide compound of formula- 1.
  • suitable coupling agent, suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention;
  • step-c) step-d) & step-f) the suitable base and the suitable solvent are same as defined in step-b) of the first aspect of the present invention.
  • a more preferred embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising;
  • An embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising reacting compound of formula-5 with compound of formula-6 or its salt in a suitable solvent optionally in presence of a suitable coupling agent and/or a suitable base to provide compound of formula- 1.
  • the suitable coupling agent, suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention.
  • the activated compound which is formed by reacting compound of formula-5 with suitable coupling agent optionally in presence of a suitable base in a suitable solvent can optionally be isolated from the reaction mixture in solid form and can be further purified from a suitable solvent or mixture of solvents. Then the activated compound can be further reacted with compound of formula-6 or its salt in a suitable solvent optionally in presence of a suitable base to provide compound of formula- 1.
  • the said activated compound is not isolated from the reaction mixture and is reacted in-situ with compound of formula-6 or its salt to provide compound of formula- 1.
  • a preferred embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising;
  • step-a) & step-c) the suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention.
  • a more preferred embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising;
  • the other embodiment of the present invention provides a process for the preparation of compound of formula-5, comprising reacting compound of formula-2 with compound of formula-4 or its salt in a suitable solvent optionally in presence of a suitable coupling agent and/or a suitable base to provide compound of formula-5.
  • the suitable coupling agent, the suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention.
  • the activated compound which is formed by reacting compound of formula-2 with a suitable coupling agent in a suitable solvent optionally in presence of a suitable base can be optionally isolated from the reaction mixture and can be further purified from a suitable solvent or mixture of solvents. Then the activated compound can be reacted with compound of formula-4 or its salt in a suitable solvent optionally in presence of a suitable base to provide compound of formula-5.
  • the compound of formula- 1 obtained by various processes of the present invention can be purified from a suitable solvent or mixture of solvents to provide pure compound of formula- 1.
  • the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof.
  • the suitable solvent is selected from ketone solvents.
  • the process developed by the present inventors is simple, safe, eco-friendly and commercially viable and involves the usage of simple and commercially available raw materials, reagents and solvents.
  • the process for the preparation of compound of formula- 1 developed by the present inventors produces highly pure compound of formula- 1 with excellent yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.
  • the compound of formula- 1 produced by various processes of the present invention is having purity of greater than 99%, preferably greater than 99.5%, more preferably greater than 99.7% by HPLC.
  • the compound of formula-3a and compound of formula-5a which are formed in the processes of the present invention are novel compounds.
  • An embodiment of the present invention provides the use of said novel compounds as intermediates for the preparation of compound of formula- 1.
  • An embodiment of the present invention provides compound of formula-3a as a solid.
  • the other embodiment of the present invention provides a crystalline polymorph of compound of formula-3a.
  • the said crystalline polymorph is characterized by its PXRD pattern having peaks at 8.9, 9.9, 12.4, 13.8, 14.2, 19.4, 19.9, 20.8, 21.7, 22.5, 24.6, 25.2, 27.9 and 30.4 ⁇ 0.2° of 2 ⁇ .
  • the said crystalline polymorph is further characterized by its PXRD pattern as illustrated in figure-9.
  • An embodiment of the present invention provides compound of formula-5a as a solid.
  • the other embodiment of the present invention provides a crystalline polymorph of compound of formula-5a, characterized by its PXRD pattern having peaks at 8.2, 13.1, 13.4, 14.1, 15.1, 16.2, 17.0, 17.6, 18.4, 19.5, 20.2, 21.4, 21.9, 22.1, 23.0, 23.3, 24.2, 24.8, 25.7, 26.5, 27.2, 28.1, 28.7, 29.8 and 30.5 ⁇ 0.2° of 2 ⁇ .
  • the said crystalline polymorph is further characterized by its PXRD pattern as illustrated in figure- 10.
  • An embodiment of the present invention provides a process for the purification of compound of formula-5, comprising;
  • the suitable base is selected from inorganic bases, organic bases or mixtures thereof; preferably inorganic bases.
  • the suitable acid is selected from "inorganic acids” such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acids” such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-
  • the suitable solvent is independently selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof.
  • a preferred embodiment of the present invention provides a process for the purification of compound of formula-5, comprising;
  • the second aspect of the present invention provides an improved process for the preparation of compound of formula- 1, comprising;
  • step-a) & step-c) reacting compound of formula-5 with compound of formula-6 or its salt in a suitable solvent optionally in presence of a suitable base and/or a suitable coupling agent to provide compound of formula- 1.
  • the suitable base is selected from but not limited to organic bases, inorganic bases, organolithium bases, organosilicon bases or mixtures thereof;
  • the suitable coupling agent can be selected from coupling agents described above;
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
  • salt in relation to compound of formula-4 and compound of formula-6 represents acid-addition salts of said compounds formed with suitable acids.
  • the "suitable acid” refers to "inorganic acids” such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acids” such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid
  • organic acids such as formic acid
  • the activated esters which are formed by reacting compound of formula-2 or compound of formula-5 with suitable coupling agents optionally in presence of a suitable base in a suitable solvent can optionally be isolated from the reaction mixture in solid form and can be further purified from a suitable solvent or mixture of solvents. Then the said activated ester can be further reacted with compound of formula-4 or its salt (in case of compound of formula-2) or with compound of formula-6 or its salt (in case of compound of formula-5) in a suitable solvent optionally in presence of a suitable base to provide compound of formula-5 and compound of formula- 1 respectively.
  • the said activated esters are not isolated from the reaction mixture and are reacted in-situ with the subsequent compounds to provide the corresponding products.
  • a preferred embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising;
  • Another preferred embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising;
  • the compound of formula-2, compound of formula-4 or its salt and compound of formula-6 or its salt utilized in various processes of the present invention can be synthesized by any of the processes known in the art or they can be procured from any commercial sources available.
  • the compound of formula-2 can be prepared according to any of the processes described in US8378105B2.
  • the compound of formula-4 or its salts and compound of formula-6 or its salts can be prepared by the processes as described below.
  • An embodiment of the present invention provides a process for the preparation of compound of formula-4 or its salts, comprising;
  • 'PG' represents amine protecting group
  • the suitable reducing agent is selected from but not limited to sodium triacetoxy borohydride (NaBH(OAc)3), sodium cyanoborohydride (NaCNBH 3 ), sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al or Vitride), diisobutylaluminium hydride (DIBAL), lithium aluminium hydride (LiAlH 4 ), sodium borohydride (NaBH 4 ), catalytic hydrogenation in presence of Pd, Pt, Rh, Raney Ni, Pt0 2 and the like;
  • the suitable Lewis acid is selected from but not limited to A1C1 3 , FeCl 3 , T1CI 4 , BF 3 , BC1 3 , BBr 3 , ZnCl 2 , SnCl 4 and the like;
  • step-c) the suitable amine protecting agent is selected based on the amine protecting group employed and it can be selected from the amine protecting agents described above. For instance, when the amine protecting group 'PG' represents Boc, then step-c) can be carried out by treating compound of formula- 10 with di-tert.butyl dicarbonate (DIBOC) optionally in presence of a suitable base selected from but not limited to organic bases, inorganic bases, organosilicon bases or their mixtures optionally in presence of a suitable solvent to provide compound of general formula- 11.
  • DIBOC di-tert.butyl dicarbonate
  • step-d) the said conversion can be carried out by carboxylation of compound of general formula- 11 with carbon dioxide (C0 2 ) to provide compound of general formula- 12.
  • the said carboxylation reaction can be carried out according to any of the processes described in ChemSusChem, 2017, 10, 3317-3332 or the procedures cited therein preferably under anhydrous
  • the suitable deprotecting agent is selected based on the protecting group employed and it can be selected from the deprotecting agents as described above.
  • the deprotection step can be performed by treating compound of general formula- 12 with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like or with acetyl chloride in combination with alcohols;
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
  • the other embodiment of the present invention provides a process for the preparation of compound of formula-6 or its salt, comprising;
  • step-a) the suitable amine protecting agent is selected from the amine protecting agents as defined above.
  • the amine protecting group 'PG' represents Boc
  • step-a) can be carried out by treating compound of formula- 13 with di- tert.butyl dicarbonate (DIBOC) optionally in presence of a suitable base selected from but not limited to organic bases, inorganic bases, organosilicon bases or their mixtures optionally in presence of a suitable solvent to provide compound of general formula- 14.
  • DIBOC di- tert.butyl dicarbonate
  • Step-b) can be carried out in presence of copper or palladium reagents selected from CuCl, CuBr, Cul, Cu(OAc) 2 , Cu 2 0, Cu(OTf) 2 , Cu(OTf) 2 PhH, Pd(OAc) 2 , Pd 2 (DBA) 3 optionally in presence of a suitable base selected from but not limited to inorganic bases, organic bases, organolithium bases, organosilicon bases;
  • This step is carried out optionally in presence of N,N'-dimethylethylamine, ⁇ , ⁇ -dimethylglycine, N,N'-dimethylamine, 1,10- phenanthroline, L-proline, L-hydroxyproline, neocuproine, 2-(hydroxymethyl)-2- methylpropane-l,3-diol, trans- 1,2-diaminocyclohexane (DACH), 1,2-dimethylethylene diamine (DMEDA), D-glucosamine, xanto
  • the suitable deprotecting agent is selected based on the protecting group employed and the deprotecting agent can be selected from the deprotecting agents as described above.
  • the deprotection step can be performed by treating compound of general formula- 15 with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq .phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like or with acetyl chloride in combination with alcohols.
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
  • the compound of formula-7 and compound of general formula- 13 utilized in the above processes can be prepared by any of the processes known in the art or they can be procured from any commercial sources available.
  • Another embodiment of the present invention provides a process for the preparation of compound of formula-6 or its salts.
  • the said process is schematically provided below.
  • 'X' represents halogen such as F, CI, Br & I;
  • 'PG' represents 'N-protecting group” or "amine protecting group”,
  • 'R' represents Ci-C 6 straight/branched chain alkyl group.
  • the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixture;
  • step-b) the hydrolysis can be carried out in presence of a suitable inorganic acid or a suitable inorganic base;
  • Step-c) can be carried out by reacting compound of general formula-D or compound of general formula- 14 with NaS0 2 Me in analogous manner to the procedure described above (see., conversion of formula- 14 to formula- 15 above);
  • the resolution process can be carried out by reacting compound of general formulae-D or E with chiral bases selected from but not limited to (R)-(+)-a- methylbenzylamine, (S)-(-)-a-methylbenzylamine, (R)-(+)-a-ethylbenzylamine, (S)-(-)-a- ethylbenzylamine, (R)-(+)-l-(2-naphthyl)ethylamine, (S)-(-)-l-(2-naphthyl)ethylamine, (R)- (-)- 1 -amino-2-propanol, (S)-(+)- 1 -amino-2-propanol, (R)-(+)- 1 -(4-bromophenyl)ethylamine, (S)-(-)-l-(4-bromophenyl)ethylamine, (S)-(
  • Step-e) can be carried out by treating compound of general formula- 15 with a suitable deprotecting agent described above under suitable conditions.
  • a suitable deprotecting agent described above under suitable conditions.
  • the deprotecting agent can be selected from acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, acetyl chloride in combination with alcohols.
  • Step-a) to step-e) can be carried out optionally in presence of suitable solvent selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
  • suitable solvent selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
  • the third aspect of the present invention provides a novel crystalline polymorph of compound of formula- 1, herein after designated as form-M.
  • the said novel crystalline form-M of compound of formula- 1 is characterized by its PXRD pattern having peaks at 5.3, 9.8, 10.6, 14.5, 17.4, 17.8, 19.6, 20.9, 22.1 , 24.3, 25.2, 26.3, 29.0, 30.0, 34.3 and 36.1 ⁇ 0.2° of 2 ⁇ .
  • the novel crystalline form-M is further characterized by its PXRD pattern having peaks at 6.3, 11.7, 12.1, 17.0, 17.5, 18.4, 20.4, 21.8, 22.9, 24.6, 25.8, 27.8, 29.7, 31.6, 38.4, 39.5 and 42.5 ⁇ 0.2° of 20.
  • the novel crystalline polymorph is further characterized by its PXRD pattern having peaks at 5.3, 9.8, 10.6, 12.1, 14.5, 17.4, 19.6, 20.4, 21.8, 22.1, 22.9, 25.2, 26.3, 30.0 and 36.1 ⁇ 0.2° of 2 ⁇ .
  • novel crystalline form-M of compound of formula- 1 is characterized by its PXRD pattern as illustrated in figure-2.
  • An embodiment of the present invention provides a process for the preparation of crystalline form-M of compound of formula- 1, comprising;
  • reaction mixture optionally heating the reaction mixture to a suitable temperature
  • reaction mixture optionally cooling the reaction mixture to a suitable temperature
  • the suitable solvent is selected from ester solvents, hydrocarbon solvents, chloro solvents, ether solvents, nitrile solvents or mixtures thereof;
  • step-b) the suitable temperature ranges from 30°C to reflux temperature of the solvent used.
  • step-d suitable temperature ranges from 0-30°C.
  • a small amount of crystalline form-M can optionally be added as seed material to the reaction mixture at any stage of step-a) to step-c) of the above described process.
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of compound of formula- 1, comprising;
  • Another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of compound of formula- 1, comprising;
  • the fourth aspect of the present invention provides a novel crystalline polymorph of compound of formula- 1, herein after designated as form-S.
  • the crystalline form-S of compound of formula- 1 of the present invention is characterized by its PXRD pattern having peaks at 10.5, 14.1, 14.7, 15.2, 15.9, 17.2, 19.6, 21.8, 24.1, 24.4, 25.3, 26.0, 27.0 and 28.7 ⁇ 0.2° of 2 ⁇ .
  • novel crystalline form-S of compound of formula- 1 is further characterized by its PXRD pattern having peaks at 10.5, 14.1, 14.7, 15.0, 15.2, 15.4, 15.9, 17.2, 19.6, 20.7, 21.8, 24.1, 24.4, 25.1, 25.3, 26.0, 27.0 and 28.7 ⁇ 0.2° of 2 ⁇ .
  • novel crystalline form-S of compound of formula- 1 is characterized by its PXRD pattern as illustrated in figure-3.
  • An embodiment of the present invention provides a process for the preparation of crystalline form-S of compound of formula- 1, comprising;
  • reaction mixture optionally heating the reaction mixture to a suitable temperature
  • reaction mixture optionally cooling the reaction mixture to a suitable temperature
  • the suitable solvent is selected from alcohol solvents, ester solvents, chloro solvents, nitrile solvents, ketone solvents, polar solvents or mixtures thereof;
  • the suitable temperature ranges from 30°C to reflux temperature of the solvent used;
  • the suitable second solvent is selected from hydrocarbon solvents, ester solvents, polar-aprotic solvents, ether solvents or mixtures thereof;
  • step-d the suitable temperature ranges from 0-30°C.
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of compound of formula- 1, comprising;
  • the fifth aspect of the present invention provides a novel crystalline polymorph of compound of formula- 1, herein after designated as crystalline form-N.
  • the said novel crystalline form-N is characterized by its PXRD pattern as illustrated in figure-4.
  • An embodiment of the present invention provides a process for the preparation of crystalline form-N of compound of formula- 1, comprising;
  • step-a) can be carried out at a suitable temperature ranges from 35°C to 70°C;
  • step-b) stirring of the reaction mixture can be done for 15 min to 10 hr;
  • step-c) the reaction mixture can be optionally cooled to a suitable temperature ranges from -50°C to 30°C.
  • a suitable solvent selected from ketone solvents, nitrile solvents, alcohol solvents such as ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol and the like or mixtures thereof can be used instead of water in step-a) of the above described process.
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of compound of formula- 1, comprising;
  • the sixth aspect of the present invention provides a novel crystalline polymorph of compound of formula- 1, herein after designated as crystalline form-L.
  • the said crystalline form-L is characterized by its PXRD pattern as illustrated in figure-7.
  • An embodiment of the present invention provides a process for the preparation of crystalline form-L of compound of formula- 1 , comprising;
  • step-a) is carried out at 25-30°C;
  • step-b) the suitable temperature ranges from 35°C to 100°C;
  • step-d) the suitable temperature ranges from -30°C to 30°C.
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-L of compound of formula- 1, comprising;
  • crystalline polymorphs of compound of formula- 1 of the present invention are prepared by the processes as illustrated in the present invention and they are useful for the preparation of various pharmaceutical compositions.
  • An embodiment of the present invention provides the use of crystalline polymorphs of compound of formula- 1 of the present invention for the preparation of pharmaceutical formulations.
  • the other embodiment of the present invention provides pharmaceutical composition comprising crystalline polymorphs of compound of formula- 1 of the present invention and at least one pharmaceutically acceptable excipient.
  • Another embodiment of the present invention provides a method of treating or preventing a condition or disease comprising administering to the patient a therapeutically effective amount of any of the crystalline polymorphs of compound of formula- 1 of the present invention.
  • the compound of formula- 1 which is used as input in the above processes for the preparation of various crystalline polymorphs of compound of formula- 1 of the present invention can be prepared by any of the processes known in the art.
  • novel crystalline polymorphs of compound of formula- 1 of the present invention can be utilized as input for the preparation of any of the known polymorphic forms of compound of formula- 1 and they can also be used as input for the preparation of other novel crystalline polymorphs of compound of formula- 1.
  • novel crystalline polymorphs of compound of formula- 1 of the present invention are useful and well suitable for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition in particular polymorphic form mentioned.
  • Such pharmaceutical compositions may comprise compound of formula- 1 present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
  • additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
  • the seventh aspect of the present invention provides a process for the preparation of compound of formula- 1, comprising;
  • 'PG' represents amine protecting group or N-protecting group
  • 'Ri' represents Ci-C 6 straight chain or branched chain alkyl group
  • step-a) coupling of compound of formula-5 with compound of formula-6 or its salt in presence of a suitable base in a suitable solvent optionally in presence of a suitable coupling agent to provide compound of formula- 1.
  • the suitable deprotecting agent is selected based on the type of the protecting group employed. In one embodiment, it can be selected from the deprotecting agents as described above.
  • the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures; and the suitable coupling agent is same as defined above in step-a) of the first aspect of the present invention.
  • step-c) the suitable acid is selected from inorganic acids and the suitable base can be selected from inorganic bases.
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
  • the compound of general formula- 16, compound of formula-2 and compound of formula-6 or its salt which are used in the above process can be obtained from any commercial sources or they can be synthesized by any of the processes known in the art.
  • the eighth aspect of the present invention provides a novel process for the preparation of compound of formula- 1, comprising;
  • step-a) the suitable coupling agent, suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention
  • step-b) the suitable acid, suitable base and the suitable solvent are same as defined in step-c) of the seventh aspect of the present invention.
  • the compound of formula-20 or its salt used in the above process can be prepared by the rocess as shown in the following synthetic scheme;
  • 'PG' represents amine protecting group or N-protecting group.
  • Compound of formula- [b] is prepared by reacting compound of formula- [a] with ⁇ , ⁇ -dimethyl hydroxylamine or its salt in presence of a suitable base in a suitable solvent optionally in presence of a suitable coupling agent.
  • a suitable coupling agent, suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention.
  • Compound of formula-20 or its salt is prepared by deprotection of compound of formula- [b] with a suitable deprotecting agent as described in the present invention optionally in presence of a suitable solvent.
  • the ninth aspect of the present invention provides alternate process for the preparation of compound of formula- 1, comprising;
  • R 2 ' represents substituted or unsubstituted aryl and the substituents are independently selected from halogens such as F, CI, Br, I, N0 2 ,
  • step-a) & step-c) the suitable coupling agent, the suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention.
  • the tenth aspect of the present invention provides a novel process for the preparation of compound of formula- 1, comprising;
  • step-a) the suitable coupling agent, the suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention
  • step-b) the suitable acid, the suitable base and the suitable solvent are same as defined in step-c) of the seventh aspect of the present invention.
  • the eleventh aspect of the present invention provides another novel process for the preparation of compound of formula- 1, comprising;
  • step-a) oxidizing compound of general formula-28 with a suitable oxidizing agent in a suitable solvent to provide compound of formula- 1.
  • step-a) the suitable coupling agent, the suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention;
  • the suitable oxidizing agent is selected from but not limited to oxone (potassium peroxymonosulfate), hydrogen peroxide (H 2 0 2 ), urea-hydrogen peroxide adduct, tert-butyl hydroperoxide (t-BuOOH or TBHP), cumene hydroperoxide (CHP), peracetic acid, trifluoroperacetic acid (TFPAA), dimethyldioxirane (DMDO), o-Iodoxybenzoic acid, m- chloroperbenzoic acid (MCPBA), molecular oxygen, (diacetoxyiodo)benzene, ammonium cerium(IV) nitrate, ⁇ 0 2 , KMn0 4 , Ru0 4 , periodic acid (H 5 IO 6 ), sodium periodate, sodium perborate, HNO 3 , sodium hypochlorite (NaOCl), calcium hypochlorite (Ca(OCl) 2 ) and the like
  • the said oxidation step is carried out optionally in presence of a titanium, vanadium or a molybdenum catalyst selected from but not limited to titanium isopropoxide, vanadium pentoxide, vanadyl acetylacetonate [VO(acac) 2 ], molybdenum acetylacetonate and the like.
  • a titanium, vanadium or a molybdenum catalyst selected from but not limited to titanium isopropoxide, vanadium pentoxide, vanadyl acetylacetonate [VO(acac) 2 ], molybdenum acetylacetonate and the like.
  • the twelfth aspect of the present invention provides another process for the preparation of compound of formula- 1, comprising;
  • 'X' represents halogen such as F, CI, Br and I;
  • step-a) the suitable coupling agent, suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention
  • step-b) the suitable solvent is same as defined in step-a) of the first aspect of the present invention.
  • This step is carried out in presence of copper or palladium reagents such as CuCl, CuBr, Cul, Cu(OAc) 2 , Cu 2 0, Cu(OTf) 2 , Cu(OTf) 2 PhH, Pd(OAc) 2 , Pd 2 (DBA) 3 optionally in presence of a suitable base selected from but not limited to inorganic bases, organic bases, organolithium bases, organosilicon bases;
  • This step is carried out optionally in presence of N,N'-dimethylethylamine, ⁇ , ⁇ -dimethylglycine, N,N'-dimethylamine, 1,10- phenanthroline, L-proline, L-hydroxyproline, neocuproine, 2-(hydroxymethyl)-2- methylpropane-l,3-diol, trans- 1,2-diaminocyclohexane (DACH),
  • the thirteenth aspect of the present invention provides a novel process for the preparation of compound of formula- 1, comprising;
  • 'R 3 ' can be selected from phenyl(Ph), benzyl (Bn) & '*'represents chiral center and the configuration at said chiral center can be (R) or (S);
  • step-a) the suitable coupling agent, the suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention
  • step-b) the conversion of compound of general formula-25 to compound of formula- 1 can be done by acid or base hydrolysis optionally in presence of a suitable solvent.
  • the acid can be selected from inorganic acids
  • the base can be selected from inorganic bases
  • the suitable solvent is same as defined in step-a) of the first aspect of the present invention.
  • This step can be carried out optionally in presence of hydrogen peroxide or lithium peroxide (LiOOH).
  • the compound of formula- 1 produced by the process of the present invention was analyzed by HPLC under the following conditions;
  • Apparatus A liquid chromatograph equipped with variable wavelength UV detector; Column: Zodiac C18 250 X 4.6 mm, 3 ⁇ (or) equivalent; Wavelength: 215 nm; Column temperature: 40°C; Auto sampler temperature: 5°C; Injection volume: 5 ⁇ ⁇ ; Diluent: Mobile phase-A: Mobile phase-B (80:20 v/v); Elution: Gradient; Sample concentration: 0.5 mg/mL; Buffer preparation: Accurately transfer 1000 mL of milli-Q-water into a suitable clean and dry beaker. Transfer accurately 1.32 gm of diammonium hydrogen ortho phosphate in 1000 mL of milli-Q-water.
  • Apparatus A liquid chromatograph equipped with variable wavelength UV detector; Column: CHIRALPAK IA-3 250 X 4.6 mm, 3 ⁇ (or) equivalent; Wavelength: 254 nm; Column temperature: 40°C; Injection volume: 15 ⁇ ⁇ ; Diluent: 0.05% triethylamine in ethanol; Elution: Isocratic; Mobile phase composition: n-Heptane:Isopropyl alcohol:Dichloromethane:TFA (70:20: 10:0.2 v/v/v/v).
  • the PXRD analysis of compounds of the present invention was carried out using BRUKER/D8 ADVANCE X-Ray diffractometer using CuKa radiation of wavelength 1.5406A 0 and at a continuous scan speed of 0.03°/min.
  • the compound of formula- 1 produced by the process of the present invention is having particle size distribution of D90 less than 300 ⁇ , preferably less than 200 ⁇ , more preferably less than 100 ⁇ .
  • An embodiment of the present invention provides compound of formula- 1 with particle size distribution of D90 less than 50 ⁇ , preferably less than 20 ⁇ .
  • Particle size distribution (PSD) method of analysis Particle size distribution (PSD) method of analysis:
  • the particle size distribution analysis was carried out by using Malvern Mastersizer 3000 instrument.
  • the compound of formula- 1 produced by the processes of the present invention can be further micronized or milled to get 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 includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
  • the present invention is schematically represented as follows;
  • 'R 2 ' represents substituted or unsubstituted aryl and the substituents wherever used can be independently selected from halogens such as F, Cl, Br & I, N0 2 and the substitution can be takes place at single or multiple positions on aryl group.
  • 'X' represents halogen such as F, CI, Br & I; and 'PG' represents 'N-protecting group" or "amine protecting group”.
  • 'PG' represents amine protecting group or N-protecting group; and represents Ci-C 6 straight chain or branched chain alkyl group.
  • 'R 2 ' represents substituted or unsubstituted aryl and the substituents wherever used can be independently selected from halogens such as F, CI, Br & I, N0 2 ; 'n' is 0 or 1 ; 'X' represents halogen.
  • '*' mark on carbon atom represents chiral center and the configuration at the said carbon atom can be (R) or (S).
  • Oxalyl chloride (29.35 gm) was slowly added to a pre-cooled mixture of compound of formula-2 (25 gm), dimethylformamide (5 ml) and tetrahydrofuran (325 ml) at 0-5°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hr at the same temperature. Slowly added the reaction mixture to a pre-cooled mixture of tetrahydrofuran (175 ml), ⁇ , ⁇ -diisopropylethyl amine (99.64 gm) and pentafluorophenol (31.21 gm) at 0-5°C.
  • Oxalyl chloride (29.35 gm) was slowly added to a pre-cooled mixture of compound of formula-2 (25 gm), dimethylformamide (5 ml) and tetrahydrofuran (325 ml) at 0-5°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30°C and stirred for 5 hr at the same temperature. A solution of pentafluorophenol (31.21 gm) in tetrahydrofuran (25 ml) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C and ⁇ , ⁇ -diisopropylethyl amine (99.64 gm) was slowly added to it at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for
  • Triethylamine 31.06 gm was added to a mixture of dimethylformamide (300 ml), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate (43.84 gm) and compound of formula-5 (30 gm) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 3 hr at the same temperature. Filtered the solid and washed with dichloromethane.
  • the obtained compound was dissolved in dichloromethane (900 ml) and the resulting solution was slowly added to a mixture of compound of formula-6a (27.95 gm), dichloromethane (300 ml) and triethylamine (11.64 gm) at 25-30°C.
  • Triethylamine (19.41 gm) was added to the reaction mixture at 25-30°C and stirred for 16 hr at the same temperature. Filtered the reaction mixture and washed with dichloromethane. Water was added to the filtrate at 25-30°C and stirred for 10 min at the same temperature.
  • Methyl ethyl ketone (25 ml) was added to compound of formula-1 (5 gm) at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the solid and washed with methyl ethyl ketone. A mixture of dichloromethane (30 ml) and methanol (30 ml) was added to the obtained solid at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with a mixture of dichloromethane and methanol. Distilled off the solvent completely from the filtrate.
  • Methyl ethyl ketone (30 ml) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5 °C and stirred for 13 hr at the same temperature. Filtered the solid, washed with methyl ethyl ketone and dried the material to get the title compound.
  • the PXRD pattern of the obtained compound is similar to the PXRD pattern of crystalline form-A illustrated in figure-6 of US8367701B2. Yield: 4.0 gm.
  • Example-6 Preparation of crystalline polymorph of compound of formula-1
  • Process-1 A mixture of compound of formula-2 (10 gm), HATU (35.17 gm), triethylamine (12.45 gm) and dimethylformamide (100 ml) was stirred for 5 hr at 25-30°C under N 2 atmosphere. Cooled the reaction mixture to 5-10°C, water was added to it and stirred for 30 min at same temperature. Filtered the solid, washed with water. The obtained compound was added to a mixture of dichloromethane (100 ml), Compound of formula-4a (17.42 gm) and triethylamine (15.58 gm) at 25-30°C under N 2 atmosphere and stirred the reaction mixture for 4 hr at same temperature.
  • Process-2 DCC (19.13 gm) and HOBt (2.5 gm) were added to a mixture of compound of formula-2 (10 gm) and dichloromethane (100 ml) at 25-30°C under N 2 atmosphere and stirred the reaction mixture for 5 hr at the same temperature. Filtered the reaction mixture and washed with dichloromethane. Distilled off the solvent completely from the filtrate and co-distilled with cyclohexane. Cyclohexane (50 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the solid, washed with cyclohexane and dried the material.
  • the obtained compound was added to a mixture of compound of formula-4a (17.4 gm), triethylamine (15.58 gm) and dichloromethane (150 ml) at 25-30°C under N 2 atmosphere and stirred the reaction mixture for 4 hr at the same temperature. Filtered the reaction mixture and washed with dichloromethane. 50% Aq.HCl solution was added to the filtrate at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the precipitated solid, washed with water and dried the material to get the title compound. Yield: 18.0 gm.
  • Process-1 Isopropyl acetate (60 ml) was added to compound of formula-1 (2 gm) at 25-30°C. Heated the reaction mixture to 35-40°C and stirred for 5 days at the same temperature. Filtered the solid and dried to get the title compound. Yield: 1.6 gm.
  • Process-2 Isopropyl acetate (90 ml) was added to compound of formula- 1 (3 gm) at 25-30°C. Form-M seed crystal (0.3 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 35-40°C and stirred for 24 hr at the same temperature. Filtered the solid and dried to get the title compound. The PXRD pattern of the obtained compound is illustrated in figure-2. Yield: 2.7 gm.
  • Process-3 Isopropyl acetate (60 ml) was added to compound of formula- 1 (2 gm) and stirred the reaction mixture for 5 days at 25-30°C. Filtered the solid and dried to get the title compound. Yield: 1.6 gm.
  • Acetonitrile (250 ml), compound of formula-4a (39.2 gm) and N,N-diisopropylethylamine (79.7 ' 1 gm) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Heated the reaction mixture to 60-65 °C and stirred for 4 hr at the same temperature. Cooled the reaction mixture to 5-10°C, 50% aqueous HCl solution (125 ml of conc.HCl in 125 ml of water) was slowly added to it and stirred the reaction mixture for 3 hr at the same temperature. Filtered the solid and washed with water.
  • HATU 31.66 gm
  • triethylamine 25.88 gm
  • HATU 31.66 gm
  • acetonitrile 250 ml
  • Water 100 ml was added to the reaction mixture at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with water.
  • the PXRD pattern of the obtained compound is illustrated in figure- 10. Yield: 50.0 gm.
  • D(0.1) is 2.80 ⁇ ; D(0.5) is 7.02 ⁇ ; D(0.9) is 20.76 ⁇ .
  • D(0.1) is 1.46 ⁇
  • D(0.5) is 3.41 ⁇
  • D(0.9) is 11.50 ⁇ .
  • n-Propanol (65 ml) was added to compound of formula-1 (5 gm) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 10 min at the same temperature. Water (10 ml) was added to the reaction mixture at 60-65 °C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the solid and dried at 25-30°C for 2 hr to get the title compound. The PXRD pattern of the obtained compound is illustrated in figure-7. Yield: 4.8 gm.
  • the obtained compound is dried at 100°C for 10 hr.
  • the PXRD pattern of the obtained compound is illustrated in figure-8. Yield: 4.4 gm.

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Abstract

La présente invention concerne divers procédés pour la préparation de l'acide (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tétrahydroisoquinoléine-6-carboxamido)-3-(3-(méthylsulfonyl)phényl)propanoïque représenté par la formule développée 1 suivante. Lesdits procédés pour la préparation du composé de formule 1 procèdent de manière à utiliser divers nouveaux composés intermédiaires. La présente invention concerne également de nouveaux polymorphes cristallins du composé de formule 1 et des procédés pour la préparation de ceux-ci.
PCT/IN2018/050552 2017-08-28 2018-08-28 Procédés pour la préparation de l'acide (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tétrahydroisoquinoléine-6-carboxamido)-3-(3-(méthylsulfonyl)phényl)propanoïque et de polymorphes de celui-ci WO2019043724A1 (fr)

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CN111171007A (zh) * 2020-02-26 2020-05-19 广州大光制药有限公司 一种立他司特中间体的合成方法
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WO2020114202A1 (fr) * 2018-12-07 2020-06-11 苏州旺山旺水生物医药有限公司 Procédé de préparation de composé lifitegrast
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CN112300139A (zh) * 2020-12-29 2021-02-02 南京佰麦生物技术有限公司 立他司特水合物晶型及其制备方法
CN112592384A (zh) * 2020-12-16 2021-04-02 广安凯特制药有限公司 一种立他司特杂质及其制备方法和去除方法
CN113072471A (zh) * 2021-03-02 2021-07-06 四川美大康华康药业有限公司 一种利非司特中间体及其制备方法
WO2021107514A3 (fr) * 2019-11-27 2021-07-22 연성정밀화학(주) Procédé de préparation de lifitegrast

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044817A1 (fr) * 2003-11-05 2005-05-19 Sunesis Pharmaceuticals, Inc. Modulateurs de l'adhesion cellulaire
WO2009139817A2 (fr) * 2008-04-15 2009-11-19 Sarcode Corporation Produit pharmaceutique cristallin et ses procédés de préparation et d'utilisation
WO2011050175A1 (fr) * 2009-10-21 2011-04-28 Sarcode Corporation Agent pharmaceutique cristallin et procédés de préparation et utilisation de celui-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044817A1 (fr) * 2003-11-05 2005-05-19 Sunesis Pharmaceuticals, Inc. Modulateurs de l'adhesion cellulaire
WO2009139817A2 (fr) * 2008-04-15 2009-11-19 Sarcode Corporation Produit pharmaceutique cristallin et ses procédés de préparation et d'utilisation
WO2011050175A1 (fr) * 2009-10-21 2011-04-28 Sarcode Corporation Agent pharmaceutique cristallin et procédés de préparation et utilisation de celui-ci

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019186520A1 (fr) * 2018-03-31 2019-10-03 Aurobindo Pharma Limited Procédé de préparation de lifitegrast
WO2019239364A1 (fr) * 2018-06-14 2019-12-19 Olon S.P.A. Procédé de préparation de lifitegrast
US11498917B2 (en) 2018-06-14 2022-11-15 Olon S.P.A. Process for the preparation of lifitegrast
WO2020114202A1 (fr) * 2018-12-07 2020-06-11 苏州旺山旺水生物医药有限公司 Procédé de préparation de composé lifitegrast
CN111747941A (zh) * 2019-03-29 2020-10-09 成都惟邦药业有限公司 一种利非司特的合成方法
CN111747941B (zh) * 2019-03-29 2023-10-10 成都惟邦药业有限公司 一种利非司特的合成方法
WO2021107514A3 (fr) * 2019-11-27 2021-07-22 연성정밀화학(주) Procédé de préparation de lifitegrast
CN111171007A (zh) * 2020-02-26 2020-05-19 广州大光制药有限公司 一种立他司特中间体的合成方法
CN111205275A (zh) * 2020-04-22 2020-05-29 南京佰麦生物技术有限公司 立他司特晶型及其制备方法
CN112592384A (zh) * 2020-12-16 2021-04-02 广安凯特制药有限公司 一种立他司特杂质及其制备方法和去除方法
CN112300139A (zh) * 2020-12-29 2021-02-02 南京佰麦生物技术有限公司 立他司特水合物晶型及其制备方法
CN113072471A (zh) * 2021-03-02 2021-07-06 四川美大康华康药业有限公司 一种利非司特中间体及其制备方法

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