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"Novel Process For The Preparation Of Lifitegrast"

Abstract: The present invention relates "to a novel process for the preparation of lifitegrast of Formula I. The present invention further provides a novel process for the purification of lifitegrast of Formula I. Formula I.

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Patent Information

Application #
Filing Date
10 October 2017
Publication Number
24/2019
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2022-09-29
Renewal Date

Applicants

MANKIND PHARMA LTD
208, OKHLA INDUSTRIAL ESTATE PHASE III NEW DELHI-110020, INDIA

Inventors

1. BHAVSAR, JIGAR TARUN KUMAR
191-E, SECTOR-4-II, IMT MANESAR GURUGRAM, HARYANA-122050, INDIA
2. TIWARI RAKESH
191-E, SECTOR-4-II, IMT MANESAR GURUGRAM, HARYANA-122050, INDIA
3. BHASHKAR, BHUWAN
191-E, SECTOR-4-II, IMT MANESAR GURUGRAM, HARYANA-122050, INDIA
4. KUMAR, ANIL
191-E, SECTOR-4-II, IMT MANESAR GURUGRAM, HARYANA-122050, INDIA

Specification

FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of lifitegrast of Formula-I and process for purification thereof. Formula-I BACKGROUND OF THE INVENTION Lifitegrast, chemically known as (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid, approved by the USFDA under the brand name Xiidra for the treatment of dry eye disease (DED). Lifitegrast is generically disclosed in US 7,314,938. US patent no. 8,080,562 and 8,378,105 discloses process for the preparation of lifitegrast as mentioned in the scheme below: Scheme 1: Formula E 10% Pd/C, HC00H/NEt3> Me0H/THF5:l Formula I US 8,080,562 also discloses crystalline forms A-E as well as amorphous form of lifitegrast and their process of preparation. US'5 62 discloses preparation of Form A.by slurrying amorphous form of lifitegrast in methyl ethyl ketone or acetonitrile. It further discloses that various crystalline forms can be prepared from Form A such as crystalline Form B is prepared by suspending the crystalline Form A in ethyl acetate; crystalline Form C is prepared by suspending crystalline Form A in ethanol; and crystalline Form D is prepared by suspending crystalline form A in water. US 8,367,701 discloses process of recrystallization of lifitegrast by slurrying lifitegrast in methyl ethyl ketone or acetonitrile followed by filtering and washing with water. US 9,085,553 discloses a process of recrystallization of lifitegrast from solution comprising acetone, preferably aqueous acetone. It also discloses an alternate method for preparing lifitegrast which includes preparation of lifitegrast ester followed by hydrolysis of said ester as shown in the scheme below: Scheme 2: o Formula I Formula J US 9,085,553 also discloses a process of preparing protected lifitegrast of Formula-J by another method as disclosed in the scheme below: Scheme 3: Formula J Formula L Although, certain published references provides processes of preparation of lifitegrast however, present invention is focussed towards the development of a novel process for the preparation of lifitegrast wherein the process involves less number of steps and hence less number of works ups and purifications resulting into quick and economical process. OBJECT OF THE INVENTION The main aspect of the present invention is to provide a novel process for the preparation of Lifitegrast. ' Another object of the present invention is to provide a novel process for the preparation of Lifitegrast which is reproducible and economical for large scale production. Another object of the present invention is to provide a novel purification process of lifitegrast to get pure lifitegrast. SUMMARY OF THE INVENTION The main aspect of the present invention provides a° process for the preparation of lifitegrast of Formula I, O 0 Formula I wherein said process comprises the steps of: r ' Formula 2 a) preparing compound of Formula 2, by condensation of protected, amine compound of Formula 3 with acid protected compound of Formula 4 or its pharmaceutical acceptable salt, CI O OH Formula 3 HoN I R Formula 4 O n to wherein PG is an amine protecting group, and R is an acid protecting group; b) de-protecting amine group of compound of Formula 2 followed by hydrolysis to give compound of Formula 5; Formula 5 c) optionally purifying compound of Formula 5; d) condensing compound of Formula 5 with benzofuran-6-carbonyl chloride in presence of base in a solvent to give lifitegrast of Formula I; and e) optionally purifying the lifitegrast of Formula I. In another aspect, the present invention provides a novel process for purification of lifitegrast of Formula!, n Formula I wherein said process comprises the steps of: (a) adding crude lifitegrast to a solvent system comprising one or more solvent wherein atleast one.solvent is water; (b) adding a base to the solvent system to form a salt of lifitegrast; (c) adjusting pH between 2 to 5 to get precipitates; and (d) isolating the precipitates and optionally recrystallizing to get lifitegrast. Another aspect of the present invention is to prepare substantially pure lifitegrast by reacting (S)-2-(537-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid of Formula 5 with benzofuran-6-carbonyl chloride, wherein said compound of Formula 5 is characterized by X-Ray powder diffraction pattern comprising peaks at about 9.55, 12.44, 17.93, 19.57, 20.97, 23.98±O.2°20. DETAILED DESCRIPTION Drawings: Fig. 1 represents X-ray powder diffraction pattern of compound of Formula 5 Fig. 2 represents Differential Scanning Calorimetry of compound of Formula 5 Definitions: As used herein, the phrase "amine protecting group" means temporary substituents which protect a potentially reactive amino functional group from undesired chemical transformations. As used herein, the phrase "acid protecting group55 means temporary substituents which protect a potentially reactive acid functional group from undesired chemical transformations. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the55 include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent5' includes mixtures of solvents. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. The present invention will now be explained' in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but'on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims. The steps of a method may be providing more details that are pertinent to • understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein. Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples. Accordingly, in one embodiment, the present invention provides a process of preparation of lifitegrast of Formula I, O 6 Formula I wherein said process comprises the steps of: a) preparing compound of Formula 2, Formula 2 by condensation of protected amine compound of Formula 3 with acid protected compound of Formula 4 or its pharmaceutical acceptable salt, H^N CI O "OH Formula 3 Formula 4 wherein PG is an amine protecting group, and R is an acid protecting group; b) de-protecting amine group of compound of Formula 2 followed by hydrolysis to i ... give compound of Formula 5; Formula 5 c) optionally purifying compound of Formula 5; d) condensing compound of Formula 5 with benzofuran-6-carbonyl chloride in presence of base in a solvent to give lifitegrast of Formula I; and e) optionally purifying the lifitegrast of Formula I. In another embodiment, the base used in preparation of lifitegrast is selected from the group comprising of primary amines, secondary amines, tertiary amines and inorganic amines. Preferably, the base used for condensing compound of Formula 5 with benzofuran-6-carbonyl chloride is selected from diisopropyl ethyl amine, pyridine, triethyl amine, dimethyl amino pyridine, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate. In another embodiment, the benzofuran-6-carbonyl chloride of Formula 7 is prepared by treating benzofuran-6-carboxylic acid of Formula 6 with acylating agent in presence of aprotic solvent, In another embodiment, the acylating agent is selected from thionyl chloride, oxalyl .chloride, phosphorus pentachloride, arid phosphoryl chloride. In other embodiment, the condensation of compound of Formula 3 with compound of Formula 4 is performed in a reaction mixture comprising of condensing agent, base and an organic solvent. In a preferred embodiment, the condensing agent selected from the group comprising of l-Ethyl^3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'- Dicyelohexylcarbodiimide (DCC), N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5- b]pyridin-1 -ylmethylene]-N-methyimethanaminium hexafluorophosphate N-oxide (HATU), Hydroxybenzotriazole (HOBt), Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU), O-CBenzotriazol-l-yO-N^^^N'-' tetramethyluronium tetrafluoroborate (TBTU), and the like. In another preferred embodiment, the base used for condensing compound of Formula 3 with compound of Formula 4 is selected from dimethyl amino pyridine (DMAP), triethyl amine (TEA), diisopropyl ethyl amine (DIPEA), 2,4,6-collidine, 1,3,5-collidine and the like. In another embodiment, the solvent used for preparation of lifitegrast is selected from polar aprotic solvents such as dimethyl formamide (DMF),. dimethyl acetamide (DMAc), N-methyl pyrrolidinone (NMP), and dimethyl sulfoxide (DMSO); halogenated solvents such as dichloromethane (DCM), dichlorobenzene, dichloroethane; esters such as ethyl acetate (EtOAc), n-butyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, pentyl acetate; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF); ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; organic amines such as secondary and tertiary amines; other solvents such as acetonitrile, xylene, toluene water; and mixture thereof. In a preferred embodiment; the above said solvent is selected from the solvents other than alcohols and each solvent used in the above said process is free, from alcohol. In a preferred embodiment, the solvent used for condensation of compound of Formula 3 with compound of Formula 4 is selected from polar aprotic solvents such as dimethyl formamide (DMF), dimethyl acetamide (DMAc), N-methyl pyrrolidinone (NMP), and dimethyl sulfoxide (DMSO) and most preferably, dimethyl formamide. In another preferred embodiment, the solvent used for condensing benzofuran-6-carbonyl chloride of Formula 7 with (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid of Formula 5 is selected from dichloromethane (DCM), dichlorobenzene, dichloroethane, ethyl acetate (EtOAc), n-butyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, pentyl acetate, acetonitrile, water or mixture thereof. Most preferably, the solvent used in above said condensation reaction is dichloromethane. In further embodiment, the base used for condensing benzofuran-6-carbonyl > chloride of Formula 7 with (S)-2-(5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid of Formula 5 is selected from dimethyl amino pyridine (DMAP), triethyl amine (TEA), diisopropyl ethyl amine (DIPEA), 2,4,6^collidine, 1,3,5-collidine, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate and the like. In another embodiment, the process of de-protection of amine group of compound of Formula 2 is performed in presence of acid and solvent wherein said acid is selected from dilute hydrochloric acid, dioxane hydrochloric acid, methanesulfonic acid, and trifluoro acetic acid. In another embodiment, the solvent used for conducting deprotection of amine group of compound of Formula 2 is selected from diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF), acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, acetonitrile and mixture thereof. In further embodiment, deprotection of amine group of compound of Formula 2 results into preparation of compound of Formula 14 which upon hydrolysis in presence of base and solvent results into preparation of compound of Formula 5. In a preferred embodiment, the base used for hydrolysis of compound of Formula 14 is selected from ammonia, diethyl amine, triethyl amine, methyl amine, dimethyl aminopyridine, pyridine, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, carbonates and bicarbonates of alkali and alkaline .earth metals, and the like. In another preferred embodiment, the solvent used for conducting hydrolysis of compound of Formula 14 is selected from diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF), acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, water and mixture thereof. In further embodiment, the compoimd of Formula 5 may be purified before proceeding to next step of condensation with compound of Formula 7 to get lifitegrast. In another embodiment, the present invention provides a process of preparation of lifitegrast of Formula I, Formula I ■wherein said process comprises the steps of: a) preparing compound of Formula 2, PG* Formula 2 O by condensation of protected amine compoimd of Formula 3 with acid protected compound of Formula 4 or its pharmaceutical acceptable salt, CI O R Formula 4 "OH PC" ^ ^ XI Formula 3 wherein PG is an amine protecting group, and R is an acid protecting group; b) de-protecting amine group of compound of Formula 2, in presence of acid followed by hydrolysis in presence of base, in absence of alcohol to give compound of Formula 5; Formula 5 c) purifying compound of Formula 5 in a solvent free from alcohol; , d) condensing compound of Formula 5 with benzofuran-6-carbonyl chloride in presence of base in a solvent togive lifitegrast of Formula I; and e) optionally purifying lifitegrast of Formula I. In one another embodiment, the present invention provides a novel process for the preparation of lifitegrast of Formula I, wherein said process comprises the steps of: a) preparation of 2-(benzofuran-6-carboriyl)-5,7-dichloro-l,2,3,4- tetrahydroisoquinoline-6-carboxylic acid of Formula 9, CI O * Formula 9 by condensation of benzdfiiran-6-carbonyl chloride, of Formula 7 with 5,7-dichloro-l523354-tetrahydroisoquinoline-6-carboxylic acid of Formula 8 in presence of acylating agent and base; CI O "OH Formula 8 b) condensation of compound of Formula 9 with (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid of Formula 10 or its pharmaceutical acceptable salt, HoN cr ^OH Formula 10 to give lifitegrast of Formula I; and c) optionally purifying lifitegrast of Formula I. As per the present invention, lifitegrast can be-prepared by two alternative methods as mentioned under scheme 4 and 5 respectively, wherein both methods involves less number of reaction steps and hence, involves minimum loss of solvents in purification and work ups. Scheme-4: o n Cl O HCIH^V^Y^S^ 0X0 U Formula 12 Boc' Formula 11 Formula 13 HCI.HN Formula 5 Formula 14 Formula I Scheme 5: Cl O HN Formula 7 Cl Formula 8 acylating agent base/organic solvent CI O HoN

Documents

Application Documents

# Name Date
1 201711035902-Other Patent Document-101017.pdf 2017-10-17
2 201711035902-Form 5-101017.pdf 2017-10-17
3 201711035902-Form 26-101017.pdf 2017-10-17
4 201711035902-Form 2(Title Page)-101017.pdf 2017-10-17
5 201711035902-Form 1-101017.pdf 2017-10-17
6 201711035902-Other Patent Document-170918.pdf 2018-09-24
7 201711035902-Form 5-170918.pdf 2018-09-24
8 201711035902-Form 3-170918.pdf 2018-09-24
9 201711035902-Form 26-170918.pdf 2018-09-24
10 201711035902-Form 2(Title Page)-170918.pdf 2018-09-24
11 201711035902-FORM 3 [16-10-2018(online)].pdf 2018-10-16
12 201711035902-Form-1-170918-.pdf 2018-10-18
13 201711035902-FORM 3 [10-07-2019(online)].pdf 2019-07-10
14 201711035902-FORM 3 [10-02-2020(online)].pdf 2020-02-10
15 201711035902-FORM 3 [22-07-2020(online)].pdf 2020-07-22
16 201711035902-FORM 3 [29-01-2021(online)].pdf 2021-01-29
17 201711035902-FORM 18 [01-02-2021(online)].pdf 2021-02-01
18 201711035902-FER.pdf 2021-10-17
19 201711035902-OTHERS [25-11-2021(online)].pdf 2021-11-25
20 201711035902-FER_SER_REPLY [25-11-2021(online)].pdf 2021-11-25
21 201711035902-COMPLETE SPECIFICATION [25-11-2021(online)].pdf 2021-11-25
22 201711035902-CLAIMS [25-11-2021(online)].pdf 2021-11-25
23 201711035902-US(14)-HearingNotice-(HearingDate-08-09-2022).pdf 2022-08-22
24 201711035902-Correspondence to notify the Controller [06-09-2022(online)].pdf 2022-09-06
25 201711035902-Written submissions and relevant documents [20-09-2022(online)].pdf 2022-09-20
26 201711035902-Annexure [20-09-2022(online)].pdf 2022-09-20
27 201711035902-RELEVANT DOCUMENTS [29-09-2022(online)].pdf 2022-09-29
28 201711035902-PETITION UNDER RULE 137 [29-09-2022(online)].pdf 2022-09-29
29 201711035902-PatentCertificate29-09-2022.pdf 2022-09-29
30 201711035902-IntimationOfGrant29-09-2022.pdf 2022-09-29
31 201711035902-RELEVANT DOCUMENTS [25-09-2023(online)].pdf 2023-09-25
32 201711035902-FORM 4 [11-10-2023(online)].pdf 2023-10-11

Search Strategy

1 wipochemicalstructuresearchE_29-05-2021.pdf
2 2021-05-2915-22-41E_29-05-2021.pdf

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