Description:FIELD OF THE INVENTION
[0001] The present invention relates to the field of medicinal chemistry and pharmaceuticals. More particularly, the present invention relates to the synthesis of Lifitegrast via transesterification and the compound thereof.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. Dry eye disease (DED) is a multifaceted disorder affecting the ocular surface, manifesting symptoms like discomfort, diminished tear quality, and chronic inflammation. This condition impacts around 20 million individuals in the United States alone. DED involves localized inflammation of the ocular surface and adjacent tissues, leading to the recruitment and activation of T cells, release of cytokines, and the production of hyperosmolar tears, resulting in sensations of eye dryness and discomfort.
[0003] Lifitegrast, is chemically known as (S)-2-(2-(benzofuran-6-carbonyl)-5,7- dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3- methylsulfonyl) phenyl)propanoic acid and is known commercially as Xiidra and sanctioned by the FDA, emerges as an effective treatment for both the signs and symptoms of dry eye. Administered as an ophthalmic solution through twice-daily eye drops, Lifitegrast, is an immune-inhibiting medication represented by the compound of Formula I, has proven effective in inhibiting interactions between Lymphocyte Function-Associated Antigen-1 (LFA-1) and the family of intercellular adhesion molecules (ICAM). Notably, Lifitegrast boasts desirable pharmacokinetic properties, featuring rapid systemic clearance.

Formula I
[0004] Lifitegrast, its salts and compositions containing Lifitegrast were first disclosed in the patent US8084047. Different processes for preparing Lifitegrast are disclosed in various patents and applications. US9085553 discloses the method of preparation of Lifitegrast and its salts wherein the ester precursor of Lifitegrast was hydrolysed with a base under biphasic conditions. Wherein, the precursor ester group is a carbon-containing moiety or a silyl containing moiety.
[0005] WO2019097547 discloses a process wherein enantiomerically pure Lifitegrast is prepared by the hydrolysis of Lifitegrast methyl ester with a base in the presence of protic solvents.

[0006] WO2019096996 discloses a transfer hydrogenolysis process for the preparation of Lifitegrast wherein benzyl (S)-2-[2-(benzofuran-6-carbonyl)-5,7-dichloro-1 ,2,3,4-tetrahydroisoquinoline-6-carboxamido]-3-[3-(methylsulfonyl)phenyl]propanoate is hydrogenated in a mixture comprising atleast one solvent selected from the group consisting of acetonitrile, a ketone solvent, an ester solvent and in the presence of a catalyst.
[0007] US20110092707 discloses process for the preparation of N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-L-phenylalanine in novel crystalline polymorphic forms A, B, C, D, and E. Wherein 6-benzofurancarboxylic acid was treated with oxalyl chloride and then reacted with N-[(5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl)carbonyl]-3-(methylsulfonyl)-L-phenylalanine phenylmethyl ester hydrochloride and methylene chloride in the presence of diisopropylethylamine to afford a condensation intermediate.

[0008] The procedures disclosed in the prior art are associated with numerous drawbacks and hence, there is increasing demand for a cost-effective, high-yield synthesis process suitable for industrial scale, to bridge the notable gap in the field, prompting the exploration of novel methods for the preparation of Lifitegrast which provides a low cost and high yield method.

OBJECTIVE OF THE INVENTION
[0009] One objective of the present invention is to provide an improved process for preparing Lifitegrast of Formula (I) or salts thereof, which is simple, economical and suitable for industrial scale up.
[0010] Another objective of the present invention is to provide a method of synthesizing alkyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate a compound of Formula V by transesterification.

Formula V
[0011] Another objective of the present invention is to provide a Lifitegrast compound with Formula I with high purity.
[0012] Another objective of the present invention is to provide a method which is cost effective and results into the high yield.
SUMMARY OF THE INVENTION
[0013] The present invention discloses a process for the preparation of Lifitegrast of Formula I from alkyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate a compound of Formula V via transesterification of Phenyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate of Formula IV

Formula IV
[0014] Accordingly, in an aspect of the present invention, the process of preparing Lifitegrast (Formula I) comprising step of
a) tert-butyl (S)-6-((1-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(1H)-carboxylate a compound of Formula IV is prepared by treatment of 2-(tert butoxy carbonyl)-5,7-dichloro 1,2,3,4 tetrahydro isoquinoline-6-carboxylic acid a compound of Formula II with benzyl-(S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride a compound of Formula III in presence of triethylamine (TEA), coupling agent and dimethylformamide

Formula II Formula III

Formula IV
b) Transesterification of compound of Formula IV to alkyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate hydrochloride a compound of Formula V using alcohol and oxalyl chloride

Formula V
Wherein R is a straight chain or branched chain alkyl preferably -CH3, -C2H5, -C3H7, -C4H9, -CH(CH3)2, -C(CH3)3.
c) Coupling of compound of Formula V with 1-benzofuran-6-carbonylchloride to form alkyl (S)-2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride compound of Formula VI

Formula VI
d) Hydrolysis of compound of Formula VI with alcohol and base and further treating it with benzyl amine to form benzyl amine salt of Compound of Formula I
e) Benzyl amine salt of compound of Formula I was treated with ethylacetate, alcohol and HCl to form Lifitegrast of compound of Formula I

Formula I
[0015] In another aspect the present invention provides a high yielding, economical, simple and commercially viable method for the preparation of Lifitegrast and its salts thereof.
[0016] In another aspect, the present invention discloses a pharmaceutical composition comprising Lifitegrast of Formula I or its salts prepared by the process described above and a pharmaceutically acceptable carrier or excipient.
[0017] In another aspect of the present invention the use of composition comprising Lifitegrast prepared by the process described above as a medicament for treating eye disorder.
[0018] Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

BRIEF DESCRIPTION OF FIGURES
[0019] FIG. 1: UPLC of compound of Formula IV prepared by example stage 1 intermediate I
[0020] FIG. 2: UPLC of methyl ester of compound of Formula V prepared by example stage I intermediate II
[0021] FIG. 3: UPLC of methyl ester of compound of Formula VI prepared by example stage II
[0022] FIG. 4: UPLC of benzylamine salt of compound of Formula I prepared by example stage III
[0023] FIG. 5: UPLC of compound of Formula I prepared by example stage IV
[0024] FIG. 6: UPLC of ethyl ester of compound of Formula V
[0025] FIG. 7: UPLC of isopropyl ester of compound of Formula V
[0026] FIG. 8: UPLC of butyl ester of compound of Formula V
[0027] FIG. 9: UPLC of propyl ester of compound of Formula V

DETAILED DESCRIPTION OF THE INVENTION
[0028] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
[0029] The following is a full description of the disclosure's embodiments. The embodiments are described in such a way that the disclosure is clearly communicated. The level of detail provided, on the other hand, is not meant to limit the expected variations of embodiments; rather, it is designed to include all modifications, equivalents, and alternatives that come within the spirit and scope of the current disclosure as defined by the attached claims. Unless the context indicates otherwise, the term "comprise" and variants such as "comprises" and "comprising" throughout the specification are to be read in an open, inclusive meaning, that is, as "including, but not limited to."
[0030] When "one embodiment" or "an embodiment" is used in this specification, it signifies that a particular feature, structure, or characteristic described in conjunction with the embodiment is present in at least one embodiment. As a result, the expressions "in one embodiment" and "in an embodiment" that appear throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, the specific features, structures, or qualities may be combined in any way that is appropriate.
[0031] Unless the content clearly demands otherwise, the singular terms "a," "an," and "the" include plural referents in this specification and the appended claims. Unless the content explicitly mandates differently, the term "or" is normally used in its broad definition, which includes "and/or."
[0032] All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0033] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0034] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0035] Accordingly, in an aspect of the present invention, the process of preparing Lifitegrast (Formula I) comprising step of
a) tert-butyl (S)-6-((1-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(1H)-carboxylate a compound of Formula IV is prepared by treatment of 2-(tert butoxy carbonyl)-5,7-dichloro 1,2,3,4 tetrahydro isoquinoline-6-carboxylic acid a compound of Formula II with benzyl-(S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride a compound of Formula III in presence of triethylamine (TEA), coupling agent and dimethylformamide

Formula II Formula III

Formula IV
b) Transesterification of compound of Formula IV to alkyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate hydrochloride a compound of Formula V using alkyl alcohol and oxalyl chloride

Formula V
Wherein R is a straight chain or branched chain alkyl preferably -CH3, -C2H5, -C3H7, -C4H9, -CH(CH3)2, -C(CH3)3.
c) Coupling of compound of Formula V with 1-benzofuran-6-carbonylchloride to form alkyl (S)-2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride compound of Formula VI

Formula VI
d) Hydrolysis of compound of Formula VI with alcohol and base and further treating it with benzyl amine to form benzyl amine salt of Compound of Formula I
e) Benzyl amine salt of Compound of Formula I was treated with ethylacetate, alcohol and HCl to form Lifitegrast of compound of Formula I

Formula I
[0036] In another embodiment, said process for the preparation of Lifitegrast of Formula I is performed from alkyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate a compound of Formula V via transesterification of Phenyl (S)-2-(5,7-dichloro 1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3 (methylsulfonyl)phenyl)propanoate of Formula IV

Formula V
[0037] In a preferred embodiment of the present invention, compound of Formula V or its salt thereof is prepared by transesterification and BOC deprotection of compound of Formula IV in the presence of oxalyl chloride and alcohol

Formula IV Formula V
[0038] In an embodiment, wherein R of Formula V, is selected from straight chain or branched chain alkyl preferably -CH3, -C2H5, -C3H7, -C4H9, -CH(CH3)2, -C(CH3)3.
[0039] In yet another embodiment, said alcohol is selected from, but not limited to the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and isobutanol.
[0040] In still another embodiment, said process is carried out in the presence of coupling agent selected from the group consisting HATU(Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), EDC.HCl (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride), CDI (1,1'-Carbonyldiimidazole), Ethyl 2-cyano-2-(hydroxylimino) acetate, HBTU (Hexafluorophosphate Benzotriazole Tetramethyl Uronium) , HCTU (O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexa?uorophosphate) or a combination thereof.
[0041] In yet another embodiment, the base is selected from the group consisting of potassium hydroxide, lithium hydroxide, sodium hydroxide, caesium hydroxide, calcium hydroxide, barium hydroxide and strontium hydroxide, as well as hydrates thereof.
[0042] In yet another embodiment, said transesterification is performed under controlled temperature ranging from about 60oC to about 85oC.
[0043] In still another embodiment, yield of the Lifitegrast compound with Formula I more than 90%
[0044] In still another embodiment, the purity of the compound more than 98%.
[0045] In an embodiment, the present invention describes the process for preparing compound of Lifitegrast of Formula I or a pharmaceutically acceptable salt thereof.
[0046] In another embodiment, the present invention discloses a pharmaceutical composition comprising Lifitegrast of Formula I or its salts prepared by the process described above and a pharmaceutically acceptable carrier or excipient.
[0047] In yet another aspect of the present invention the use of composition comprising Lifitegrast prepared by the process described above as a medicament for treating eye disorder.
[0048] In an embodiment, the present invention describes the process for preparing compound of Formula 1 or a pharmaceutically expectable salt thereof. The process of the present invention is outlined in Scheme 1:
[0049] Scheme 1:



EXAMPLE
The present invention is further explained in the form of the following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.
Stage-I- Intermediate-I
[0050] Preparation of tert-butyl (S)-6-((1-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(1H)-carboxylate

100 g (0.28 mol) of 2-(Tert butoxy carbonyl)-5,7-dichloro 1,2,3,4 tetrahydro isoquinoline 6 carboxylic acid was dissolved in 500 ml Dimethyl Formamide. Added 138 g (0.38 mol) HATU followed by 200 ml (1.44 mol) triethyl amine under stirring at room temperature. Added 106 gm (0.28 mol) Benzyl (S)-2-amino-3-[3- (methylsulfonyl) phenyl] propionate hydrochloride, stirred at RT for 5-6 hrs. The reaction mass was quenched in water after completion of the reaction, stirred for 1 hr & filtered the product and washed with water. The product was dried under a vacuum for 12 hours at 40- 45°C. Dry wt.:- 182 g, Yield: 94% & Purity: 98% (FIG.. 1)
[0051] Intermediate-II
Preparation of methyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride

Dissolved 180 g (0.27 mol.) tert-butyl (S)-6-((1-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(1H)-carboxylate intermediate in 800 ml methanol. Added 171 g (1.35 mol) Oxalyl chloride slowly at 25-35°C. The reaction mass was heated to reflux and the progress of the reaction was monitored by UPLC. The reaction mass was cooled to 25-30°C after completion of the reaction. The product was filtered and washed with 100 ml Methanol. The product was dried under a vacuum at 50-55°C. (FIG.. 2)
Dry weight – 132 g, Yield: 93% and Purity: 97%

[0052] Stage II
Preparation of methyl (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate:

Charged 42.0 g (0.26 mol) benzofuran 6-carboxylic acid and 215 ml of DCM, added 1 ml DMF. Charged 42 g (0.34 mol) of oxalyl chloride drop-wise at 25-30 °C. Digested for 1 hour at 25-30 °C, the progress and the completion of the reaction was monitored by UPLC. The reaction mass was used as such for the next step (FIG. 3)
Charged 130 g (0.25 mol) methyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride intermediate & 725 ml DCM in another RBF. Cooled the reaction mass. Added 150 ml triethylamine (1.08 mol.) followed by above Benzofuran-6-carbonyl chloride solution in DCM at low temperature and stirred at room temperature for 2 hours. After completion of reaction, water was added to the reaction mass followed by layer separation, the organic layer was washed with water, and the separated organic layer was concentrated under a vacuum to give foamy solid. The solid was stirred in 600ml 20% ethyl acetate in cyclohexane and then filtered and washed with Cyclohexane, dried under a vacuum at 50-55°C for 8 hours.
Dry Wt.: 145 gm, Yield: 94% Purity: 95%
[0053] Stage III
Preparation of benzyl amine salt of Lifitegrast

Dissolved 140 g (0.22 mol) methyl (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate intermediate in 825 ml Methanol, cooled to 5-10°C. Added a solution of 13.4 gm (0.33 mol) sodium hydroxide dissolved in 165 ml of water at 0 to 5°C in 1 hour. The reaction mass was maintained at 0 to 5°C. After completion of the reaction, methanol was distilled out, to the reaction mass added 825 ml water and 825 ml ethyl acetate, stirred and layers were separated. The aqueous layer was washed with 400 ml x 2 times ethyl acetate. 825 ml ethyl acetate was added to the aqueous layer, acidified with dilute hydrochloric acid and layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under a vacuum to give the foamy solid. The solid was dissolved in 1500 ml ethyl acetate & isopropanol mixture to this benzyl amine (25 gm) was added and heated and stirred at 70-75°C for 1 hour. The reaction mass was then cooled to room temperature, stirred for 5-6 hours and the precipitated solid was filtered (FIG. 4)
Obtained compound benzyl amine salt of Lifitegrast Dry Wt.: 100 g Yield: 71%; HPLC purity: 99.8%
[0054] Stage IV

100 g benzyl amine salt of Lifitegrast (LFT-IV/ Stage III) was added to 1.0 L ethyl acetate and 500 ml water, acidified with hydrochloric acid and stirred at room temperature. The layers were separated and the aqueous layer was extracted with 500 ml ethyl acetate. The organic layer was washed 3 times with 500 ml water and concentrated under a vacuum to give solid. Isolated solid was dried in an air oven at about 40-45°C (FIG. 5).
Dry Wt.: 80 g Yield: 94%; HPLC Purity: 99.8%, Chiral purity: 99.9% (R-isomer; 0.1%)
[0055] It is to be noted that the isolation of compound of Formula IV by conventional process is difficult due to its characterization, which affects the overall purity of final compound of Formula I. The process of the present invention involves trans-esterification of compound of Formula IV to aliphatic alcohol esters of compound of Formula V (FIG. 6-FIG. 9). This improves solid properties, ease process such as filtration, crystallization and purification and in turn improve the purity of compound of Formula I. The present invention employs cheaper and easily available raw materials and eliminates use of hazardous reagents. It is, therefore, efficient, economical and safe to carry out. For the above reasons, it is also suitable for industrial scale-up.
[0056] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions, or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
[0057] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
, Claims:1. A process for preparing compound of Lifitegrast of Formula (I) or a salt thereof via comprising the steps of:
a) preparing tert-butyl (S)-6-((1-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(1H)-carboxylate a compound of Formula IV by treatment of 2-(tert butoxy carbonyl)-5,7-dichloro 1,2,3,4 tetrahydro isoquinoline-6-carboxylic acid a compound of Formula II with benzyl-(S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride a compound of Formula III in presence of triethylamine (TEA) and coupling agent and dimethylformamide

Formula II Formula III

Formula IV
b) performing the transesterification of compound of Formula IV to alkyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate hydrochloride to a compound of Formula V using alkyl alcohol and oxalyl chloride

Formula V
wherein R is a straight chain or branched chain alkyl preferably -CH3, -C2H5, -C3H7, -C4H9, -CH(CH3)2, -C(CH3)3.
c) Coupling of compound of Formula V with 1-benzofuran-6-carbonylchloride to form alkyl (S)-2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride compound of Formula VI

Formula VI
d) Performing the hydrolysis of compound of Formula VI with alcohol and base and further treating it with benzyl amine to form benzyl amine salt of Compound of Formula I
e) treating the Benzyl amine salt of Compound of Formula I with ethylacetate, alcohol and HCl to form Lifitegrast of compound of Formula I

Formula I

2. The process of preparation of alkyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate a compound of Formula V via transesterification of Phenyl (S)-2-(5,7-dichloro 1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3 (methylsulfonyl)phenyl)propanoate of Formula IV

Formula V
3. The process as claimed in claim 1 and 2, wherein the compound of Formula V or its salt thereof is prepared by transesterification and BOC deprotection of compound of Formula IV in the presence of oxalyl chloride and alcohol

Formula IV Formula V

4. The compound of Formula V as claimed in claim 3, wherein R is selected from straight chain or branched chain alkyl preferably -CH3, -C2H5, -C3H7, -C4H9, -CH(CH3)2, -C(CH3)3.

5. The process as claimed in claim 1, wherein said alcohol is selected from, but not limited to the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and isobutanol.

6. The process as claimed in claim 1, wherein said process carried out in the presence of coupling agent selected from the group consisting consisting HATU(Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), EDC.HCl (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride), CDI (1,1'-Carbonyldiimidazole), Ethyl 2-cyano-2-(hydroxylimino) acetate, HBTU (Hexafluorophosphate Benzotriazole Tetramethyl Uronium) , HCTU (O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’!-tetramethyluronium hexa?uorophosphate) or a combination thereof preferably HATU

7. The process as claimed in claim 1, wherein the yield of the Lifitegrast compound with Formula I is more than 90%

8. The process as claimed in claim 1, wherein the purity of the compound more than 98%.

9. The process as claimed in claim 1, wherein the base is selected from the group consisting of potassium hydroxide, lithium hydroxide, sodium hydroxide, caesium hydroxide, calcium hydroxide, barium hydroxide and strontium hydroxide, as well as hydrates thereof.

10. A compound of Formula I prepared by process as claimed in claim 1 and 2.

11. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.